From c810027e19f0720fea560bb4121c0630ce312383 Mon Sep 17 00:00:00 2001 From: MarvinDo Date: Thu, 21 Dec 2023 15:08:20 +0100 Subject: [PATCH] added tests & minor fixes & improvements --- src/common/functions.py | 7 +- .../tests/data/heredivar_test_data.sql | 1396 +---------------- src/frontend_celery/tests/data/variant_52.vcf | 4 +- .../test_classification_calculation.py | 86 +- .../tests/functional/test_variant_io.py | 3 + .../tests/functional/test_variant_routes.py | 501 +++++- .../webapp/templates/variant/check.html | 1 + .../webapp/variant/variant_routes.py | 24 +- 8 files changed, 594 insertions(+), 1428 deletions(-) diff --git a/src/common/functions.py b/src/common/functions.py index 55b5ad01..117b855e 100644 --- a/src/common/functions.py +++ b/src/common/functions.py @@ -225,13 +225,16 @@ def curate_chromosome(chrom): def curate_position(pos): is_valid = True - if pos is None: + if pos is None or pos.strip() == '': is_valid = False return None, is_valid pos = str(pos).replace(',', '').replace('.', '').strip() allowed = "0123456789" is_valid = all(c in allowed for c in pos) - return int(pos), is_valid + if is_valid: + return int(pos), is_valid + else: + return pos, is_valid def curate_sequence(seq, allowed = "ACGT-"): if seq is None: diff --git a/src/frontend_celery/tests/data/heredivar_test_data.sql b/src/frontend_celery/tests/data/heredivar_test_data.sql index 94ffcf6b..a0c2759e 100644 --- a/src/frontend_celery/tests/data/heredivar_test_data.sql +++ b/src/frontend_celery/tests/data/heredivar_test_data.sql @@ -63,455 +63,23 @@ UNLOCK TABLES; -- Add data for schemes -- LOCK TABLES `classification_scheme` WRITE; -INSERT INTO `classification_scheme` (`id`,`name`,`display_name`,`type`,`reference`,`is_active`,`is_default`) VALUES (1,'none','No scheme','none','#',1,0), -(2,'acmg_standard','ACMG standard','acmg','https://pubmed.ncbi.nlm.nih.gov/25741868/',1,0), -(3,'acmg_TP53','ACMG gene specific: TP53','acmg','https://pubmed.ncbi.nlm.nih.gov/33300245/',1,0), -(4,'acmg_CDH1','ACMG gene specific: CDH1','acmg','https://pubmed.ncbi.nlm.nih.gov/30311375/',0,0), -(5,'task-force','VUS-task-force standard','task-force','#',1,0), -(6,'task-force-brca','VUS-task-force gene specific: BRCA1/2','task-force','#',0,0), -(21,'enigma-brca1','ClinGen ENIGMA BRCA1 v1.0.0','acmg-enigma-brca1','https://submit.ncbi.nlm.nih.gov/api/2.0/files/ng7aawit/clingen_brca1_v1.0.0.pdf/?format=attachment',1,0), -(22,'enigma-brca2','ClinGen ENIGMA BRCA2 v1.0.0','acmg-enigma-brca2','https://submit.ncbi.nlm.nih.gov/api/2.0/files/pbpwnhly/clingen_brca2_v1.0.0.pdf/?format=attachment',1,0), -(23,'enigma-palb2','ClinGen ACMG PALB2 v1.0.0','acmg-enigma-palb2','https://submit.ncbi.nlm.nih.gov/api/2.0/files/wru0e6pu/clingen_palb2_v1.0.0.pdf/?format=attachment',1,0), -(24,'enigma-tp53','ClinGen ACMG TP53 v1.4.0','acmg-enigma-tp53','https://submit.ncbi.nlm.nih.gov/api/2.0/files/kc3grqd4/clingen_tp53_v1.4.0.pdf/?format=attachment',1,0), -(25,'enigma-brca1','ClinGen ENIGMA BRCA1 v1.0.0','acmg-enigma-brca1','https://cspec.genome.network/cspec/ui/svi/doc/GN092',0,0), -(26,'enigma-palb2','ClinGen ENIGMA PALB2 v1.0.0','acmg-enigma-palb2','https://cspec.genome.network/cspec/ui/svi/doc/GN077',0,0), -(27,'enigma-palb2','ClinGen ENIGMA PALB2 v1.0.0','acmg-enigma-palb2','https://cspec.genome.network/cspec/ui/svi/doc/GN077',0,0), -(28,'enigma-ATM','ClinGen ACMG ATM v1.1.0','acmg-enigma-atm','#',1,0), -(29,'acmg_svi','ACMG SVI adaptation','acmg','#',0,0), -(30,'acmg_svi','ACMG SVI adaptation','acmg-svi','#',1,1), -(31,'acmg_standard','ACMG standard','acmg','https://pubmed.ncbi.nlm.nih.gov/25741868/',1,0); +INSERT INTO `classification_scheme` VALUES +(1,'none','v1.0.0','No scheme','none','#',1,0), +(2,'acmg_standard','v1.0.0','ACMG standard','acmg','https://pubmed.ncbi.nlm.nih.gov/25741868/',1,0), +(3,'acmg_TP53','v1.0.0','ACMG gene specific: TP53','acmg','https://pubmed.ncbi.nlm.nih.gov/33300245/',1,0), +(4,'acmg_CDH1','v1.0.0','ACMG gene specific: CDH1','acmg','https://pubmed.ncbi.nlm.nih.gov/30311375/',0,0), +(5,'task-force','v1.0.0','VUS-task-force standard','task-force','#',1,0), +(6,'task-force-brca','v1.0.0','VUS-task-force gene specific: BRCA1/2','task-force','#',1,0), +(21,'enigma-brca1','v1.0.0','ClinGen ENIGMA BRCA1 v1.0.0','acmg-enigma-brca1','https://submit.ncbi.nlm.nih.gov/api/2.0/files/ng7aawit/clingen_brca1_v1.0.0.pdf/?format=attachment',1,0), +(22,'enigma-brca2','v1.0.0','ClinGen ENIGMA BRCA2 v1.0.0','acmg-enigma-brca2','https://submit.ncbi.nlm.nih.gov/api/2.0/files/pbpwnhly/clingen_brca2_v1.0.0.pdf/?format=attachment',1,0), +(23,'enigma-palb2','v1.0.0','ClinGen ACMG PALB2 v1.0.0','acmg-enigma-palb2','https://submit.ncbi.nlm.nih.gov/api/2.0/files/wru0e6pu/clingen_palb2_v1.0.0.pdf/?format=attachment',1,0), +(24,'enigma-tp53','v1.4.0','ClinGen ACMG TP53 v1.4.0','acmg-enigma-tp53','https://submit.ncbi.nlm.nih.gov/api/2.0/files/kc3grqd4/clingen_tp53_v1.4.0.pdf/?format=attachment',1,0), +(28,'enigma-ATM','v1.1.0','ClinGen ACMG ATM v1.1.0','acmg-enigma-atm','#',1,0), +(30,'acmg_svi','v1.0.0','ACMG SVI adaptation','acmg-svi','https://pubmed.ncbi.nlm.nih.gov/25741868/',1,1); UNLOCK TABLES; --- --- Dumping data for table `classification_criterium` --- - LOCK TABLES `classification_criterium` WRITE; -INSERT INTO `classification_criterium` (`id`,`classification_scheme_id`,`name`,`description`,`is_selectable`,`relevant_info`) VALUES (1,2,'PVS1','Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease \n\nCaveats: \n- Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7) \n- Use caution interpreting LOF variants at the extreme 3\' end of a gene \n- Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact \n- Use caution in the presence of multiple transcripts',1,''), -(2,2,'PS1','Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. \n\nExample: Val->Leu caused by either G>C or G>T in the same codon \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level',1,''), -(3,2,'PS2','De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. \n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.',1,''), -(4,2,'PS3','Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. \n\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.',1,''), -(5,2,'PS4','The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. \n\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. \n\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.',1,''), -(6,2,'PM1','Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.',1,''), -(7,2,'PM2','Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. \n\nCaveat: Population data for indels may be poorly called by next generation sequencing.',1,''), -(8,2,'PM3','For recessive disorders, detected in trans with a pathogenic variant. \n\nNote: This requires testing of parents (or offspring) to determine phase.',1,''), -(9,2,'PM4','Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.',1,''), -(10,2,'PM5','Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. \n\nExample: Arg156His is pathogenic, now you observe Arg156Cys. \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.',1,''), -(11,2,'PM6','Assumed de novo, but without confirmation of paternity and maternity.',1,''), -(12,2,'PP1','Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\nNote: May be used as stronger evidence with increasing segregation data.',1,''), -(13,2,'PP2','Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.',1,''), -(14,2,'PP3','Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.',1,''), -(15,2,'PP4','Patient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.',1,''), -(16,2,'PP5','Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation.',1,''), -(17,2,'BA1','Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC.',1,''), -(18,2,'BS1','Allele frequency is greater than expected for disorder.',1,''), -(19,2,'BS2','Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.',1,''), -(20,2,'BS3','Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.',1,''), -(21,2,'BS4','Lack of segregation in affected members of a family. \n\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.',1,''), -(22,2,'BP1','Missense variant in a gene for which primarily truncating variants are known to cause disease',1,''), -(23,2,'BP2','Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern.',1,''), -(24,2,'BP3','In-frame deletions/insertions in a repetitive region without a known function',1,''), -(25,2,'BP4','Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.',1,''), -(26,2,'BP5','Variant found in a case with an alternate molecular basis for disease.',1,''), -(27,2,'BP6','Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation.',1,''), -(28,2,'BP7','A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.',1,''), -(29,3,'PVS1','Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease \n\n Use SVI-approved decision tree to determine the strength of this criterion (refer to Abou Tayoun et al. for more details).',1,''), -(30,3,'PS1','Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. \n\n Use original description with the following additions: \n PS1: \n - Must confirm there is no difference in splicing using RNA data. \n - Can only be used to compare to variants classified as Pathogenic or Likely Pathogenic by the TP53 VCEP (see ClinVar for VCEP classifications). \n\n PS1_Moderate: \n - Must confirm there is no difference in splicing using a metapredictor. \n - Can only be used to compare to variants classified as Pathogenic or Likely Pathogenic by the TP53 VCEP (see ClinVar).',1,''), -(31,3,'PS2','De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. \n\n Use SVI-approved scoring system to determine the strength of this criterion (refer to Table 2 from original publication: PMC8374922 (linked above) for more details)',1,''), -(32,3,'PS3','Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. \n\n The following additions have been made by the TP53 ACMG specification: \n - PS3: transactivation assays in yeast demonstrate a low functioning allele (≤20% activity) AND there is evidence of dominant negative effect and loss-of-function OR there is a second assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays).\n\n - PS3_Moderate: transactivation assays in yeast demonstrate a partially functioning allele (>20% and ≤75% activity) AND there is evidence of dominant negative effect and loss-of-function OR there is a second assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays).\n\n - PS3_Moderate: there is no data available from transactivation assays in yeast BUT there is evidence of dominant negative effect and loss-of-function AND there is a second assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays).\n\n ==> Refer to Figure 1 from original publication: PMC8374922 (linked above) for more details.',1,''), -(33,3,'PS4','The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. \n\n Use SVI-approved scoring system to determine the strength of this criterion (refer to Table 3 from original publication: PMC8374922 (linked above) for more details). This criterion cannot be applied when a variant also meets BA1 or BS1. Refrain from considering probands who have another pathogenic variant(s) in a highly penetrant cancer gene(s) that is a logical cause for presentation. \n\n Caveat: \n Please be mindful of the risk of clonal hematopoieses of indeterminate potential with TP53 variants (Coffee et al., 2017, Weitzel et al., 2017). One should take care to ensure that probands have germline and not mosaic somatic TP53 variants.',1,''), -(34,3,'PM1','Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. \n\n Located in a mutational hotspot defined as: \n - Variants within the following codons on protein NP_000537.3: 175, 273, 245, 248, 282, 249. \n - Variants seen in cancerhotspots.org (v2) with >10 somatic occurrences (recommendation from the ClinGen Germline/Somatic Variant Curation Subcommittee).',1,''), -(35,3,'PM2','Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. \n\n Caveat: Population data for indels may be poorly called by next generation sequencing. \n\n PM2_Supporting: absent from population databases (gnomAD (most up-to-date non-cancer dataset) is the preferred population database at this time http:#gnomad.broadinstitute.org).',1,''), -(36,3,'PM3','Excluded.',0,''), -(37,3,'PM4','Excluded.',0,''), -(38,3,'PM5','Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. \n\n Example: Arg156His is pathogenic, now you observe Arg156Cys. \n\n PM5: novel missense change at an amino acid residue where at least two other different missense changes determined to be pathogenic by the TP53 VCEP have been seen before. PM5_Supporting: novel missense change at an amino acid residue where a different missense change determined to be pathogenic by the TP53 VCEP has been seen before. \n\n Both criteria require the following additions: \n - Grantham should be used to compare the variants, and the variant being evaluated must have equal to or higher score than the observed pathogenic variants. \n - Splicing should be ruled out using a metapredictor. \n - This criterion cannot be applied when a variant also meets PM1.',1,''), -(39,3,'PM6','Assumed de novo, but without confirmation of paternity and maternity. \n\n Use SVI-approved scoring system to determine the strength of this criterion (refer to Table 2 from original publication: PMC8374922 (linked above) for more details).',1,''), -(40,3,'PP1','Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\n PP1: co-segregation with disease is observed in 3–4 meioses in one family. \n PP1_Moderate: co-segregation with disease is observed in 5–6 meioses in one family. \n PP1_Strong: co-segregation with disease is observed >7 meioses in >1 family.',1,''), -(41,3,'PP2','Excluded.',0,''), -(42,3,'PP3','Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). \n\n Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. \n\n PP3: Use original description with the following additions: \n - For missense variants, use a combination of BayesDel (≥0.16) and optimised Align-GVGD (C55-C25). \n - For splicing variants, use a metapredictor. \n\n PP3_Moderate: for missense variants, use a combination of BayesDel (≥0.16) and optimized Align-GVGD (C65).',1,''), -(43,3,'PP4','Excluded.',0,''), -(44,3,'PP5','Excluded.',0,''), -(45,3,'BA1','Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC.\n\n Allele frequency is ≥0.1% in a non-founder population with a minimum of five alleles (gnomAD (most up-to-date non-cancer dataset)) is the preferred population database at this time http:#gnomad.broadinstitute.org).',1,''), -(46,3,'BS1','Allele frequency is greater than expected for disorder. \n\n Allele frequency is ≥0.03% and <0.1% in a non-founder population with a minimum of five alleles (gnomAD (most up-to-date non-cancer dataset) is the preferred population database at this time http:#gnomad.broadinstitute.org).',1,''), -(47,3,'BS2','Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.\n\n BS2: observed in a single dataset in ≥8 females, who have reached at least 60 years of age without cancer (i.e. cancer diagnoses after age 60 are ignored). \n\n BS2_Supporting: observed in a single dataset in 2–7 females, who have reached at least 60 years of age without cancer. \n\n Caveat: Be mindful of the risk of clonal hematopoiesis of indeterminate potential with TP53 variants (Coffee et al., 2017, Weitzel et al., 2017). Individuals with mosaic somatic TP53 variants should not be included as evidence for BS2.',1,''), -(48,3,'BS3','Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. \n\n - BS3: transactivation assays in yeast demonstrate a functional allele or super-transactivation (>75% activity) AND there is no evidence of dominant negative effect and loss-of-function OR there is a second assay showing retained function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays). \n\n - BS3_Supporting: transactivation assays in yeast demonstrate a partially functioning allele (>20% and ≤75% activity) AND there is no evidence of dominant negative effect and loss-of-function OR there is a second assay showing retained function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays). \n\n - BS3_Supporting: there is no data available from transactivation assays in yeast BUT there is no evidence of dominant negative effect and loss-of-function AND there is a second assay showing retained function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays). \n\n ==> Refer to Figure 1 from original publication: PMC8374922 (linked above) for more details.',1,''), -(49,3,'BS4','Lack of segregation in affected members of a family. \n\n The variant segregates to opposite side of the family meeting LFS criteria, or the variant is present in >3 living unaffected individuals (at least two of three should be female) above 55 years of age.',1,''), -(50,3,'BP1','Excluded',0,''), -(51,3,'BP2','Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern. \n\n Variant is observed in trans with a TP53 pathogenic variant (phase confirmed), or there are three or more observations with a TP53 pathogenic variant when phase is unknown (at least two different TP53 pathogenic variants). The other observed pathogenic variants must have been classified using the TP53-specific guidelines.',1,''), -(52,3,'BP3','Excluded',0,''), -(53,3,'BP4','Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) \n\n Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. \n\n Same rule description with the following additions: \n - For missense variants, use a combination of BayesDel (<0.16) and optimized Align-GVGD (C15-C0). \n - For splicing variants, use a metapredictor.',1,''), -(54,3,'BP5','Excluded',0,''), -(55,3,'BP6','Excluded',0,''), -(56,3,'BP7','A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. \n\n Same description with the following additions: \n - Splicing should be ruled out using a metapredictor. \n - If a new alternate site is predicted, compare strength to native site in interpretation.',1,''), -(57,4,'PVS1','Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease \n\n - Very strong: Per ClinGen SVI guidelines with the exception of canonical splice sites \n - Strong: Per ClinGen SVI guidelines. Use the strong strength of evidence for canonical splice sites. \n caveat: \n CDH1 exonic deletions or tandem duplications of in-frame exon truncations in NMD-resistant zone located upstream the most 3\' well characterized pathogenic variant c.2506G>T (p.Glu836Ter). Use moderate strength if premature stop is downstream of this variant \n - Moderate: Per ClinGen SVI guidelines. \n caveats: \n 1. G to non-G variants disrupting the last nucleotide of an exon \n 2. Canonical splice sites located in exons demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site) - Supporting: Per ClinGen SVI guidelines. \n\n Additional comment: \n RNA analysis is recommended for splicing alterations, and if the RNA evidence does not support the prediction, the strength should be updated PP3 cannot be applied for canonical splice sites',1,''), -(58,4,'PS1','Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. \n\n Example: Val->Leu caused by either G>C or G>T in the same codon \n Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level \n\n Additional comment: \n Variant must not impact splicing.',1,''), -(59,4,'PS2','De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. \n \n Strength specifications: \n - Very strong: ≥2 patients with DGC and/or LBC w/parental confirmation - Strong: 1 patient with DGC and/or LBC w/parental confirmation \n Additional comment: \n Use ClinGen\'s de novo point system for a highly specific phenotype (see Table S2 from original publication linked at the top of the page)',1,''), -(60,4,'PS3','Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. \n\n Strength specifications: \n - Strong: RNA assay demonstrating abnormal out-of-frame transcripts \n - Supporting: RNA assay demonstrating abnormal in-frame transcripts \n Additional comment: \n This rule can only be applied to demonstrate splicing defects.',1,''), -(61,4,'PS4','The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. \n\n Strength specifications: \n - Very strong: 16 families meet HDGC criteria \n - Strong: 4 families meet HDGC criteria \n - Moderate: 2 families meet HDGC criteria \n - Supporting: 1 family meets HDGC criteria \n\n Additional comment: \n This rule assumes 30% penetrance in individuals with pathogenic variants. For example, if the variant in observed in 3 families, at least one of those families need to meet criteria for HDGC in order to apply this rule. PS4 cannot be applied to variants that meet BS1 or BA1',1,''), -(62,4,'PM1','Excluded.',0,''), -(63,4,'PM2','Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. \n\n <1/100,000 alleles in gnomAD cohort, if present in ≥2 individuals, must be present in <1/50,000 alleles within a sub-population \n\n Additional comment: \n Use gnomAD to determine allele frequency. Beware of technical limitations that can inaccurately represent allele frequency in this population database',1,''), -(64,4,'PM3','Excluded',0,''), -(65,4,'PM4','Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. \n\n Additional comment: \n No rule specification proposed. Variant example - CDH1 c.2647T>C (p.Ter883Glnext*29)',1,''), -(66,4,'PM5','Excluded',0,''), -(67,4,'PM6','Assumed de novo, but without confirmation of paternity and maternity. \n\n Strength specification: \n - Very strong: ≥4 patients with DGC and/or LBC w/o parental confirmation \n - Strong: ≥2 patients with DGC and/or LBC w/o parental confirmation \n - Moderate: 1 patient with DGC and/or LBC w/o parental confirmation \n\n Additional comment: \n Use ClinGen\'s de novo point system for a highly specific phenotype (See Table S2 of original publication linked at the top of this page)',1,''), -(68,4,'PP1','Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\n Strength specification: \n - Strong: ≥7 meioses across ≥2 families \n - Moderate: 5-6 meioses across ≥1 families \n - Supporting: 3-4 meioses across ≥1 families \n\n Additional comment: \n Based strength of rule code on number of meioses across one or more families.',1,''), -(69,4,'PP2','Excluded',0,''), -(70,4,'PP3','Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). \n\n Strength specification: \n - Moderate: Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/RNA predictions \n - Supporting: At least 3 in silico splicing predictors in agreement (.Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder) \n\n Additional comment: \n Rule code is only for non-canonical splicing variants. Code also does not apply to last nucleotide of exon 3 (c.387G). Do not use protein-based computational prediction models for missense variants',1,''), -(71,4,'PP4','Use PS4 in place of PP4.',1,''), -(72,4,'PP5','Excluded',0,''), -(73,4,'BA1','Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC. \n\n MAF cutoff of 0.2% \n\n Additional comment: \n 99.99% CI, subpopulation must have a minimum of 5 alleles present.',1,''), -(74,4,'BS1','Allele frequency is greater than expected for disorder. \n\n Stand alone: MAF cutoff of 0.1% \n\n Additional comment: \n 99.99% CI, subpopulation must have a minimum of 5 alleles present',1,''), -(75,4,'BS2','Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age. \n\n Strength specification: \n - Strong: Variant seen in ≥10 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC \n - Supporting: Variant seen in ≥3 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC ',1,''), -(76,4,'BS3','Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. \n Functional RNA studies demonstrating no impact on transcript composition. \n\n Additional comment: \n This rule can only be used to demonstrate lack of splicing and can be downgraded based on quality of data.',1,''), -(77,4,'BS4','Lack of segregation in affected members of a family. \n\n Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. \n\n Additional comment: \n Beware of the presence of phenocopies (e.g., breast cancer) that can mimic lack of segregation. Also, families may have more than one pathogenic variant contributing to another AD disorder',1,''), -(78,4,'BP1','Excluded',0,''), -(79,4,'BP2','Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern. \n\n Strength specifications: \n - Strong: Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors \n - Supporting: Variant is observed in cis (or phase is unknown) w/ a pathogenic variant \n\n Additional comment: \n Evidence code is dependent on strength of data. Take consideration of quality of sequencing data when applying code. Note that code requires knowledge of individuals\' phenotype. Therefore, data from population databases should only be used when phenotypic info is available.',1,''), -(80,4,'BP3','Excluded',0,''), -(81,4,'BP4','Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) \n\n Splicing predictions only. At least 3 in silico splicing predictors in agreement (Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder) \n\n Additional comment: \n This rule can only be used when splicing predictions models suggest no impact on protein. Do not use protein based computational prediction models for missense. variants',1,''), -(82,4,'BP5','Variant found in a case with an alternate molecular basis for disease. \n\n Additional comment: \n This applies if a P/LP variant is identified in an alternate gene known to cause HDGC (e.g., CTNNA1)',1,''), -(83,4,'BP6','Excluded',0,''), -(84,4,'BP7','A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. \n\n Synonymous variants where nucleotide is not highly conserved, variant is the reference nucleotide in 1 primate and/or >3 mammal species \n\n Additional comment: \n Note the CDH1 rule specification does not require a benign in silico splice prediction. This allows use with BP4, as appropriate, to classify variants meeting both criteria as likely benign ',1,''), -(85,5,'1.1','Allele frequency ≥ 1 % (MAF ≥ 0.01) in large populations like Caucasians, Africans or Asians. \n\n CAVE: Allele freuqency ≥ 1 % in subpopulations with low mixed gene pool (e. g. Finnish populations, Foundermutations) does NOT suffice this criterium.',1,''), -(86,5,'1.2','Variants with a multifactorial calculated pobability of < 0,001 (< 0,1 %) to be pathogenic. \n\n CAVE: Currently only applicable to BRCA1/2.',1,''), -(87,5,'1.3','Variants in high risk genes which occur in at least 10 individuals within suitable groups of non-diseased individuals (e. g. FLOSSIES).',1,''), -(88,5,'2.1','Allele frequency between 0.5 and 1 % (MAF 0.005–0,01) in large populations like Caucasians, Africans or Asians. \n\n CAVE: Allele freuqency between 0.5 and 1 % in subpopulations with low mixed gene pool (e. g. Finnish populations, Foundermutations) does NOT suffice this criterium.',1,''), -(89,5,'2.2','Either exonic variants (A), which lead to the substitution of an amino acid (missense variants), or small in-frame insertions/ deletions, which lead to insertions/deletions of one or amino acid(s) and whose a priori probability for pathogenicity is for pathogenicity is ≤ 2% (A-GVGD analysis, http:#priors.hci.utah.edu/PRIORS/), and (B) synonymous variants, if these variants (A, B) are likely to be pathogenic according to bioinformatic prediction programs the splicing result with a high probability and (A) are outside the relevant and (A) are located outside of the relevant functional domains defined by the VUS task-force (see tables A5.1–5.9 from the original proposal linked at the top of this page). For the non-BRCA1/2 genes, the above variants must be In large populations with an allele frequency of. 0.001 ≤ MAF < 0.01 (0.1-1%).',1,''), -(90,5,'2.3','Synonymous substitutions or intronic variants, which do not contain mRNA aberrations in the form of exon deletions/ duplications or monoallelic expression of the wild-type transcript in RNA analyses. This applies even if they are likely to alter the splice-result according to bioinformatic prediction programs (for programs and thresholds, see Appendix A1 of the original proposal liked at the top of this page).',1,''), -(91,5,'2.4','Variants that occur in the same gene with a clearly pathogenic variant in trans (co-occurrence). It must be confirmed that a homozygous or compound heterozygous genotype is associated with a known clinically distinct phenotype.',1,''), -(92,5,'2.5','Variants with a multifactorial calculated probability to be pathogenic of 0.001-0.049. \n\n CAVE: Does only apply to BRCA1/2.',1,''), -(93,5,'2.6','Exonic variants which cause an amino acid change equal to a known class 1 variant, but encode a different nucleotide change. Additionally, the variant must not show a conspicious splice prediction.',1,''), -(94,5,'2.7','Missense variants which have information from functional analyses (or similar). These, however, do not suffice for a multifactorial classification. Additionally, the variant was previously classified by expert panels like ENIGMA or the ClinGen-expert-group as class 2',1,''), -(95,5,'2.8','Suitable functional analyses do not show a loss of function or functional relevance. Additionally there must not be contradictory data. \n\n Comment: The suitable functional analyses are dependent on the gene of the variant.',1,''), -(96,5,'2.9','Paired LOH-analyses in blood or tumor samples show a loss of the allele which contains the variant under consideration. This was proven among tumor tissue (BC or OC).',1,''), -(97,5,'2.10','Variants within genes of intermediate risk without hints to potential function loss. These variants must also occour in at least 20 individuals of suitable non-diseased cohorts (e. g. FLOSSIES) \n\n CAVE: Exceptions are possible in case of frequent foundermutations (e. g. CHEK2, c.1100del).',1,''), -(98,5,'3.1','A special case in which the criteria clearly state a certain classification. However, the variant is listed among the special cases of the genes or other exceptions occur (see table 5 of the original proposal linked at the top of the page)',1,''), -(99,5,'3.2','Variants with controversial data with regards to its classification.',1,''), -(100,5,'3.3','Variants which can be found within -20 to +3 bp and -3 to +8 bp from an exon/intron border. This applies only if there is no in-vitro mRNA analysis and criteria 4.3, 4.4 or 2.6 do not apply.',1,''), -(101,5,'3.4','Exon duplications without additional analyses (e. g. cDNA analyses, break-point analyses, ...)',1,''), -(102,5,'3.5','Variants with a multifaktorial calculated pathogenicity probability between 0.05 and 0.949. \n\n CAVE: This criterium only applies to BRCA1/2 variants.',1,''), -(103,5,'4.1','Variants with a multifaktorial calculated pathogenicity probability between 0.95 and 0.99. \n\n CAVE: This criterium only applies to BRCA1/2 variants.',1,''), -(104,5,'4.2','Variants which encode an early stop of the protein synthesis (nonsense- or frameshift variants). In addition, variants must not cause damage to known clinical relevant functional protein domains as long as the induced stop codon is found approximately 50 bp upstream from the last exon-exon-junction. \n\n Comment: If there is at least one exon-exon-junction complex downstream of the new, early stop codon, the early one would be able to recruit the Upf1 and, thus, induce nonsense-mediated decay (NMD))',1,''), -(105,5,'4.3','Intronic variants at position ± 1,2 or a G to A/T or C change at the last position of the exon. Apply this criterium if there is a positive splice prediction and there is no mRNA analysis. \n\n CAVE: Applies to BRCA1/2 variants at the last position of the exon only if the first 6 bases within the intron are not equal to \"GTRRGT\". \n\n Exceptions: \n - A cryptic spice site (AG/GT) is activated by the variant and the (predicted) new exon yields in-frame splicing --> class 3 \n - A transcript with (predicted) skipped exon(s) exists as a relevant alternatively spliced transcipt --> class 3 \n - The (predicted) skipped exon(s) is spliced in-frame and does not contain known functional domains --> class 3',1,''), -(106,5,'4.4','Variants which cause the same amino acid change as a known class 5 pathogenic missence variant, but is characterized by another nucleotide change. Also, it is required that there is no prediction of abberant splicing.',1,''), -(107,5,'4.5','In-frame deletions which cause the loss of a class 5 missence variant and which disrupt or cause the loss of funcionally important protein domains.',1,''), -(108,5,'4.6','In-frame insertions which were verified via in-vitro mRNA analyses, that disrupt functionally important protein domains.',1,''), -(109,5,'4.7','Variants which cause a change in the tranlation initiation codon (AUG, Methionin). Additionally, there must not be evidence (e. g. close alternative start-codon) for an alternative classification.',1,''), -(110,5,'4.8','Variants which do have information from functional analyses, clinical data, or other evidence that do, however, not suffice for a multifactorial classification and which were classified as class 4 by expert panels like ENIGMA or ClinGen.',1,''), -(111,5,'4.9','Variants which have functional analyses that depict loss of function or another functional relevance and which do not have contradictory information.',1,''), -(112,5,'5.1','Nonsense- or frameshift variants which induce an early stop codon. This stop codon prevents the expression of known relevant functional protein domains.',1,''), -(113,5,'5.2','Variants with a multifactorial calculated probability to be pathogenic of more than 0.99. \n\n CAVE: Only applies to BRCA1/2.',1,''), -(114,5,'5.3','Splice variants which were shown to induce a frame shift that causes an early stop of the proteinbiosynthesis and, thus, prevents the expression of known relevant functional protein domains. This was proven via in-vitro mRNA analyses. It is also important that NO wildtype transcript of the mutated allele is detectable (monoallelic expression).',1,''), -(115,5,'5.4','Splice variants in which an invitro mRNA analysis has detected an in-frame deletion/insertion that leads to the interruption or loss of a known clinically relevant domain or to a change in the protein structure which functionally inactivates the protein. It is also important that NO wildtype transcript of the mutated allele is detectable (monoallelic expression).',1,''), -(116,5,'5.5','Copy number deletions which cause the disruption or loss of (an) exon(s) which contain clinically relevant functional domain(s) or which cause a predicted inactivation of known clinically relevant functional domains due to a frame shift.',1,''), -(117,5,'5.6','Copy number duplications of any size which were proven (with lab-analyses) to duplicate one or multiple exons that cause a frame shift and, thus, inactivate known clinically relevant functional protein domains.',1,''), -(118,6,'1.1','Allele frequency ≥ 1 % (MAF ≥ 0.01) in large populations like Caucasians, Africans or Asians. \n\n CAVE: Allele freuqency ≥ 1 % in subpopulations with low mixed gene pool (e. g. Finnish populations, Foundermutations) does NOT suffice this criterium.',1,''), -(119,6,'1.2','Variants with a multifactorial calculated pobability of < 0,001 (< 0,1 %) to be pathogenic. \n\n CAVE: Currently only applicable to BRCA1/2.',1,''), -(120,6,'1.3','Variants in high risk genes which occur in at least 10 individuals within suitable groups of non-diseased individuals (e. g. FLOSSIES).',1,''), -(121,6,'2.1','Allele frequency between 0.5 and 1 % (MAF 0.005–0,01) in large populations like Caucasians, Africans or Asians. \n\n CAVE: Allele freuqency between 0.5 and 1 % in subpopulations with low mixed gene pool (e. g. Finnish populations, Foundermutations) does NOT suffice this criterium.',1,''), -(122,6,'2.2','Either exonic variants (A), which lead to the substitution of an amino acid (missense variants), or small in-frame insertions/ deletions, which lead to insertions/deletions of one or amino acid(s) and whose a priori probability for pathogenicity is for pathogenicity is ≤ 2% (A-GVGD analysis, http:#priors.hci.utah.edu/PRIORS/), and (B) synonymous variants, if these variants (A, B) are likely to be pathogenic according to bioinformatic prediction programs the splicing result with a high probability and (A) are outside the relevant and (A) are located outside of the relevant functional domains defined by the VUS task-force (see tables A5.1–5.9 from the original proposal linked at the top of this page). For the non-BRCA1/2 genes, the above variants must be In large populations with an allele frequency of. 0.001 ≤ MAF < 0.01 (0.1-1%).',1,''), -(123,6,'2.3','Synonymous substitutions or intronic variants, which do not contain mRNA aberrations in the form of exon deletions/ duplications or monoallelic expression of the wild-type transcript in RNA analyses. This applies even if they are likely to alter the splice-result according to bioinformatic prediction programs (for programs and thresholds, see Appendix A1 of the original proposal liked at the top of this page).',1,''), -(124,6,'2.4','Variants that occur in the same gene with a clearly pathogenic variant in trans (co-occurrence). It must be confirmed that a homozygous or compound heterozygous genotype is associated with a known clinically distinct phenotype.',1,''), -(125,6,'2.5','Variants with a multifactorial calculated probability to be pathogenic of 0.001-0.049. \n\n CAVE: Does only apply to BRCA1/2.',1,''), -(126,6,'2.6','Exonic variants which cause an amino acid change equal to a known class 1 variant, but encode a different nucleotide change. Additionally, the variant must not show a conspicious splice prediction.',1,''), -(127,6,'2.7','Missense variants which have information from functional analyses (or similar). These, however, do not suffice for a multifactorial classification. Additionally, the variant was previously classified by expert panels like ENIGMA or the ClinGen-expert-group as class 2',1,''), -(128,6,'2.8','Suitable functional analyses do not show a loss of function or functional relevance. Additionally there must not be contradictory data. \n\n Comment: The suitable functional analyses are dependent on the gene of the variant.',1,''), -(129,6,'2.9','Paired LOH-analyses in blood or tumor samples show a loss of the allele which contains the variant under consideration. This was proven among tumor tissue (BC or OC).',1,''), -(130,6,'2.10','Variants within genes of intermediate risk without hints to potential function loss. These variants must also occour in at least 20 individuals of suitable non-diseased cohorts (e. g. FLOSSIES) \n\n CAVE: Exceptions are possible in case of frequent foundermutations (e. g. CHEK2, c.1100del).',1,''), -(131,6,'3.1','A special case in which the criteria clearly state a certain classification. However, the variant is listed among the special cases of the genes or other exceptions occur (see table 5 of the original proposal linked at the top of the page)',1,''), -(132,6,'3.2','Variants with controversial data with regards to its classification.',1,''), -(133,6,'3.3','Variants which can be found within -20 to +3 bp and -3 to +8 bp from an exon/intron border. This applies only if there is no in-vitro mRNA analysis and criteria 4.3, 4.4 or 2.6 do not apply.',1,''), -(134,6,'3.4','Exon duplications without additional analyses (e. g. cDNA analyses, break-point analyses, ...)',1,''), -(135,6,'3.5','Variants with a multifaktorial calculated pathogenicity probability between 0.05 and 0.949. \n\n CAVE: This criterium only applies to BRCA1/2 variants.',1,''), -(136,6,'4.1','Variants with a multifaktorial calculated pathogenicity probability between 0.95 and 0.99. \n\n CAVE: This criterium only applies to BRCA1/2 variants.',1,''), -(137,6,'4.2','Variants which encode an early stop of the protein synthesis (nonsense- or frameshift variants). In addition, variants must not cause damage to known clinical relevant functional protein domains as long as the induced stop codon is found approximately 50 bp upstream from the last exon-exon-junction. \n\n Comment: If there is at least one exon-exon-junction complex downstream of the new, early stop codon, the early one would be able to recruit the Upf1 and, thus, induce nonsense-mediated decay (NMD))',1,''), -(138,6,'4.3','Intronic variants at position ± 1,2 or a G to A/T or C change at the last position of the exon. Apply this criterium if there is a positive splice prediction and there is no mRNA analysis. \n\n CAVE: Applies to BRCA1/2 variants at the last position of the exon only if the first 6 bases within the intron are not equal to \"GTRRGT\". \n\n Exceptions: \n - A cryptic spice site (AG/GT) is activated by the variant and the (predicted) new exon yields in-frame splicing --> class 3 \n - A transcript with (predicted) skipped exon(s) exists as a relevant alternatively spliced transcipt --> class 3 \n - The (predicted) skipped exon(s) is spliced in-frame and does not contain known functional domains --> class 3',1,''), -(139,6,'4.4','Variants which cause the same amino acid change as a known class 5 pathogenic missence variant, but is characterized by another nucleotide change. Also, it is required that there is no prediction of abberant splicing.',1,''), -(140,6,'4.5','In-frame deletions which cause the loss of a class 5 missence variant and which disrupt or cause the loss of funcionally important protein domains.',1,''), -(141,6,'4.6','In-frame insertions which were verified via in-vitro mRNA analyses, that disrupt functionally important protein domains.',1,''), -(142,6,'4.7','Variants which cause a change in the tranlation initiation codon (AUG, Methionin). Additionally, there must not be evidence (e. g. close alternative start-codon) for an alternative classification.',1,''), -(143,6,'4.8','Variants which do have information from functional analyses, clinical data, or other evidence that do, however, not suffice for a multifactorial classification and which were classified as class 4 by expert panels like ENIGMA or ClinGen.',1,''), -(144,6,'4.9','Variants which have functional analyses that depict loss of function or another functional relevance and which do not have contradictory information.',1,''), -(145,6,'5.1','Nonsense- or frameshift variants which induce an early stop codon. This stop codon prevents the expression of known relevant functional protein domains.',1,''), -(146,6,'5.2','Variants with a multifactorial calculated probability to be pathogenic of more than 0.99. \n\n CAVE: Only applies to BRCA1/2.',1,''), -(147,6,'5.3','Splice variants which were shown to induce a frame shift that causes an early stop of the proteinbiosynthesis and, thus, prevents the expression of known relevant functional protein domains. This was proven via in-vitro mRNA analyses. It is also important that NO wildtype transcript of the mutated allele is detectable (monoallelic expression).',1,''), -(148,6,'5.4','Splice variants in which an invitro mRNA analysis has detected an in-frame deletion/insertion that leads to the interruption or loss of a known clinically relevant domain or to a change in the protein structure which functionally inactivates the protein. It is also important that NO wildtype transcript of the mutated allele is detectable (monoallelic expression).',1,''), -(149,6,'5.5','Copy number deletions which cause the disruption or loss of (an) exon(s) which contain clinically relevant functional domain(s) or which cause a predicted inactivation of known clinically relevant functional domains due to a frame shift.',1,''), -(150,6,'5.6','Copy number duplications of any size which were proven (with lab-analyses) to duplicate one or multiple exons that cause a frame shift and, thus, inactivate known clinically relevant functional protein domains.',1,''), -(749,21,'PVS1','ACMG summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nNull variant (nonsense, frameshift, splice site (donor/acceptor +/-1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\nIn alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5_PTC code (See Appendix D for details).\nInstructions:\nSee Specifications Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the BRCA1 and BRCA2 PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor +/- 1,2)) - organized by exon. See Appendix Figure 3,4 and Table 5 for further justification.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.',1,''), -(750,21,'PS1','ACMG summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nStrong:\nApply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1, for exonic and intronic variants with same predicted impact on splicing, as a previously classified pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \nSee Specifications Table 5 and Appendix E, J and K for details.\n\nModerate:\nApply PS1_Moderate, for predicted missense substitutions, where previously classified likely pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1_Moderate, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\nSupporting:\nApply PS1_Supporting, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\nInstructions:\nFor both missense and splicing scenarios, (Likely) Pathogenic variant classification should be assigned using VCEP specifications.\nFor application of PS1 for splicing predictions, see Specifications Table 5. The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the variant and the previously classified pathogenic variant should also be considered before PS1 code application for splicing prediction.',1,''), -(751,21,'PS2','ACMG summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''), -(752,21,'PS3','ACMG summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''), -(753,21,'PS4','ACMG summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies, p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.\nModification Type: Clarification,Gene-specific\n\nInstructions:\nCase dataset should be ethnicity and country-matched to control dataset. If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). Do not use Proband Counting as originally described.',1,''), -(754,21,'PM1','ACMG summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''), -(755,21,'PM2','ACMG summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-Specific modifications:\nAbsent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.\nModification Type: Gene-specific\n\nInstructions:\nObservation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth <25 at region around the variant.',1,''), -(756,21,'PM3','ACMG summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nApply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3_Strong = ≥4 points\nPM3 = 2 points\nPM3_Supporting = 1 point\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nVariant under assessment must be sufficiently rare (meet PM2_Supporting, or PM2 not applicable).\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\nFor related individuals score only most severe presentation.\nAlso see Specifications Table 6 for additional stipulations',1,''), -(757,21,'PM4','ACMG summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''), -(758,21,'PM5','ACMG summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic, now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nProtein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.\n\nInstructions:\nOnly applied to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). See Specifications Table 4, provided as a separate searchable excel file, for PM5_PTC codes applicable for predicted termination codon variants - organized by exon.',1,''), -(759,21,'PM6','ACMG summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''), -(760,21,'PP1','ACMG summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\nPP1_Very Strong - LR>350:1\nPP1_Strong - LR>18.7:1\nPP1_Moderate - LR>4.3:1\nPP1 - LR >2.08:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.\nStipulation: to apply code as Pathogenic Very Strong, VUS should have bioinformatically predicted (or experimentally proven) effect on protein or mRNA splicing. If co-segregation score is from a single family, or several families from an isolated population, assess the possibility of a different causative pathogenic variant.',1,''), -(761,21,'PP2','ACMG summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: High frequency of benign missense variants.',0,''), -(762,21,'PP3','ACMG summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nApply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857.\nApply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.\nSee Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''), -(763,21,'PP4','ACMG summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\n\nGene-specific modifications:\nBreast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4_Very Strong - LR>350:1\nPP4_Strong - LR>18.7:1\nPP4_Moderate - LR>4.3:1\nPP4 - LR >2.08:1 \nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\nSee Specifications Table7 and Appendix B for details.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''), -(764,21,'PP5','ACMG summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(765,21,'BA1','ACMG summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nFilter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''), -(766,21,'BS1','ACMG summary:\nAllele frequency is greater than expected for disorder.\n\nStrong:\nFilter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nSupporting:\nFilter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''), -(767,21,'BS2','ACMG summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nApplied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See Specifications Table 8 for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2 = ≥ 4 points\nBS2_Moderate = 2 points\nBS2_Supporting = 1 points\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nSee Specifications Table 8 for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\nAlso see Specifications Table 8 for additional stipulations.',1,''), -(768,21,'BS3','ACMG summary:\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of no damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''), -(769,21,'BS4','ACMG summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nLack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\nBS4_VeryStrong - LR <0.00285:1\nBS4 - LR <0.05:1\nBS4_Moderate - LR <0.23:1\nBS4_Supporting - LR 0.23-0.48:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.',1,''), -(770,21,'BP1','ACMG summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\n\nGene-specific modifications:\nApply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact. Missense prediction not applicable.',1,''), -(771,21,'BP2','ACMG summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\nNot Applicable\nComments: Applied only in the context of BS2.',0,''), -(772,21,'BP3','ACMG summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details',0,''), -(773,21,'BP4','ACMG summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nMissense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.15 AND SpliceAI ≤0.1).\nSilent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).\nIntronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''), -(774,21,'BP5','ACMG summary:\nVariant found in a case with an alternate molecular basis for disease.\n\nGene-specific modifications:\nUse ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5_VeryStrong - LR <0.00285:1\nBP5_Strong - LR <0.05:1\nBP5_Moderate - LR <0.23:1\nBP5 - LR 0.23-0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast-ovarian cancer risk genes have no specific phenotype.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''), -(775,21,'BP6','ACMG summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(776,21,'BP7','ACMG summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nStrong:\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile - mRNA assay only. Apply as BP7 (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nSupporting:\nSilent variant inside a (potentially) clinically important functional domain, IF BP4 met.\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\nSee Specifications Figure1A and Appendix J for additional details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained. Not applicable for missense variants inside a (potentially) clinically important functional domain as they may still impact protein function through the amino acid change.\nFollowing convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI ≤0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. See Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''), -(777,22,'PVS1','ACMG summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nNull variant (nonsense, frameshift, splice site (donor/acceptor +/-1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nIn alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5_PTC code (See Appendix D for details).\nSee Specifications Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the BRCA1 and BRCA2 PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor ±1,2)) – organized by exon. See Appendix Figure 5,6 and Table 5 for further justification.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.',1,''), -(778,22,'PS1','ACMG summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nStrong:\nApply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1, for exonic and intronic variants with same predicted impact on splicing, as a previously classified pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \nSee Specifications Table 5 and Appendix E, J and K for details.\n\nModerate:\nApply PS1_Moderate, for predicted missense substitutions, where a previously classified likely pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1_Moderate, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\nSupporting:\nApply PS1, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\n\nInstructions:\nFor both missense and splicing scenarios, (Likely) Pathogenic variant classification should be assigned using VCEP specifications.\nFor application of PS1 for splicing predictions, see Specifications Table 5. The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the variant and the established pathogenic variant should also be considered before PS1 code application for splicing prediction.',1,''), -(779,22,'PS2','ACMG summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot Applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''), -(780,22,'PS3','ACMG summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''), -(781,22,'PS4','ACMG summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies, p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.\n\nInstructions:\nCase dataset should be ethnicity and country-matched to control dataset. If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). Do not use Proband Counting as originally described.',1,''), -(782,22,'PM1','ACMG summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''), -(783,22,'PM2','ACMG summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nAbsent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.\n\nInstructions:\nObservation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth <25 at region around the variant.',1,''), -(784,22,'PM3','ACMG summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nStrong:\nApply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\nPM3_Strong = ≥4 points\n\nModerate:\nApply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\nPM3 = 2 points\n\nSupporting:\nApply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\nPM3_Supporting = 1 point\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nVariant under assessment must be sufficiently rare (meet PM2_Supporting, or PM2 not applicable).\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\nFor related individuals score only most severe presentation.\nAlso see Specifications Table 6 for additional stipulations',1,''), -(785,22,'PM4','ACMG summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''), -(786,22,'PM5','ACMG summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic, now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nProtein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.\n\nInstructions:\nOnly applied to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). See Specifications Table 4, provided as a separate searchable excel file, for PM5_PTC codes applicable for predicted termination codon variants - organized by exon.',1,''), -(787,22,'PM6','ACMG summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''), -(788,22,'PP1','ACMG summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\nApply weight as per Bayes Score:\nPP1_Very Strong - LR>350:1\nPP1_Strong - LR>18.7:1\nPP1_Moderate - LR>4.3:1\nPP1 - LR >2.08:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.\nStipulation: to apply code as Pathogenic Very Strong, VUS should have bioinformatically predicted (or experimentally proven) effect on protein or mRNA splicing. If co-segregation score is from a single family, or several families from an isolated population, assess the possibility of a different causative pathogenic variant.',1,''), -(789,22,'PP2','ACMG summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: High frequency of benign missense variants.',0,''), -(790,22,'PP3','ACMG summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nApply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.30). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40, BRCA2 DNA binding aa 2481-3186.\nApply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.\nSee Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''), -(791,22,'PP4','ACMG summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\n\nGene-specific modifications:\nBreast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4_Strong - LR>18.7:1\nPP4_Very Strong - LR>350:1\nPP4_Moderate - LR>4.3:1\nPP4 - LR >2.08:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\nSee Specifications Table7 and Appendix B for details.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''), -(792,22,'PP5','ACMG summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.',0,''), -(793,22,'BA1','ACMG summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nFilter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''), -(794,22,'BS1','ACMG summary:\nAllele frequency is greater than expected for disorder.\n\nStrong:\nFilter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nSupporting\nFilter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''), -(795,22,'BS2','ACMG summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nApplied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See Specifications Table 8 for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\nBS2 = ≥ 4 points\nBS2_Moderate = 2 points\nBS2_Supporting = 1 points\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nSee Specifications Table 8 for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\nAlso see Specifications Table 8 for additional stipulations.',1,''), -(796,22,'BS3','ACMG summary:\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of no damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''), -(797,22,'BS4','ACMG summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nLack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\nBS4_VeryStrong - LR <0.00285:1\nBS4 - LR <0.05:1\nBS4_Moderate - LR <0.23:1\nBS4_Supporting - LR 0.23-0.48:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.',1,''), -(798,22,'BP1','ACMG summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\n\nGene-specific modifications\nApply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40, BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact. Missense prediction not applicable.',1,''), -(799,22,'BP2','ACMG summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\nNot Applicable\nComments: Applied only in the context of BS2.',0,''), -(800,22,'BP3','ACMG summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details',0,''), -(801,22,'BP4','ACMG summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nMissense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.18 AND SpliceAI ≤0.1).\nSilent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).\nIntronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40, BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''), -(802,22,'BP5','ACMG summary:\nVariant found in a case with an alternate molecular basis for disease.\n\nStrong\nUse ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5_VeryStrong - LR <0.00285:1\nBP5_Strong - LR <0.05:1\nBP5_Moderate - LR <0.23:1\nBP5 - LR 0.23-0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast-ovarian cancer risk genes have no specific phenotype.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''), -(803,22,'BP6','ACMG summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(804,22,'BP7','ACMG summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nStrong\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile - mRNA assay only. Apply as BP7_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40, BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.\n\nSupporting\nSilent variant inside a (potentially) clinically important functional domain, IF BP4 met.\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\nSee Specifications Figure1A and Appendix J for additional details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40, BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained. Not applicable for missense variants inside a (potentially) clinically important functional domain as they may still impact protein function through the amino acid change.\nFollowing convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI ≤0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. See Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''), -(805,23,'PVS1','ACMG Summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nInstructions:\n - Use PALB2 PVS1 Decision Tree Per PALB2 Exon Map and PALB2 PVS1 Guide \n - PVS1: Predicted splice defect \n - PVS1_Strength(RNA): Observed splice defect \n - The default RefSeq transcript for nucleotide (c.) annotation is NM_024675.3/ENST00000261584.8. Several naturally occurring alternate splicing isoforms have been described. Yet, after careful examination, none of them is considered a candidate rescue transcript (very low contribution to overall expression, not coding proteins predicted functional, or both). In keeping with that, we have considered that all presumed LoF events (PVS1 decision tree specifications) occur in biologically relevant transcript(s).\n - WD40 beta propeller and the Coiled-coil domain (CC) are considered indispensable for PALB2 protein function. \n - PVS1 alterations that are predicted to escape NMD, but that adversely affect the WD40 domain can be granted PVS1 (as opposed to PVS1_Strong as the recommended baseline. The following evidence supports this strength change: \n - The WD40 domain interacts with many different protein partners that are involved in the double strand break repair pathway3\n - Two different C-terminal truncating mutations (c.3549C>A and c.3549C>G) resulting in loss of the last 3 amino acids [p.(Tyr1183Ter)], were identified in trans with PALB2 stop-gain variants in three unrelated FA (FA-N) patients4\n - The PALB2 WD40 toroidal structure is “sealed” in the seventh blade by interaction of the C-terminal strand with the incomplete N-terminal blade. The last four residues of PALB2 (Y1183, H1184, Y1185, and S1186) are directly involved in this interaction (molecular Velcro hydrogen bonding)00. This is the rationale for the clinical relevance of the last 4 amino acids of the protein.\n - Alterations predicted to lead to in frame losses adversely affecting the WD40 structure/function are found in trans with LoF PALB2 alterations in Fanconi Anemia patients4\n - Exon 10 donor: c.3113+5G>C (biallelic with c.395delT)\n - Exon 12 donor: c.3350+4A>G (biallelic with c.2393_2394insCT)\n - LoF alterations are rare in GnomAD in all exons\n - GnomAD v2.1 accessed 5/30/2019\n - Total Variants (includes splice acceptor/donor-conservative)\n - 1418 variants\n - 336,349 carriers\n - LoF Flag (excludes splice acceptor/donor-conservative)\n - 95 variants (6.7%)\n - 239 carriers (.07%)\n - PVS1 can be applied as per the PVS1 decision tree.\n - PVS1_Variable(RNA) shall be used for observed splice defects, whether from canonical +/-1,2 positions or other spliceogenic regions (including mid-exonic missense/synonymous variants that cause splice defects) with baseline weight as per the below decision tree. Weight can be further modified based on the quality of the RNA study including consideration of concepts such as:\n - Starting material (where patient material is preferable to in vitro minigene)\n - Use of NMD inhibitors where translation does occur such as cell lines56\n - Primer design (to make sure it\'s comprehensive to capture possible multicassette events)\n - Method of quantification \n - where e.g. capillary electrophoresis is preferable to estimation by gel band density\n - where SNP analysis is most preferred (where analysis of exonic SNPs and their relative presence in aberrant and WT transcripts is informative)\n - Quantification (where complete effects should have increased weight over incomplete effects)\n - Specific guidance on the use of RNA evidence in variant assessment is not a gene-specific consideration for PALB2 at this time, therefore discretion is left to assessors until further guidance is provided for this general concept from the Sequence Variant Interpretation group.',1,''), -(806,23,'PS1','ACMG Summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nUse PALB2 PS1 Splicing table\n\nInstructions:\n - Protein: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2\n - RNA: See PALB2 PS1 Table \n - * Prerequisite for all: The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. \n - (Likely) pathogenic variant should be assigned classification using VCEP specifications. \n - For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the VUA and (likely) pathogenic variant should also be considered before application of this code. \n - Canonical dinucleotide refers to donor and acceptor dinucleotides in reference transcript/s used for curation. \n - Designated donor and acceptor site motifs ranges should be based on position weight matrices for intron category. \n - For GT-AG introns these are defined as follows: the donor site motif, last 3 bases of the exon and 6 nucleotides of intronic sequence adjacent to the exon, acceptor site motif, first base of the exon and 20 nucleotides upstream from the exon boundary. Consider other motif ranges for non GT-AG introns. \n - # If relevant, splicing data for a pathogenic variant outside a canonical dinucleotide may be used to update a PVS1 decision tree, and hence the applicable PVS1 code for a canonical dinucleotide variant.',1,''), -(807,23,'PS2','ACMG Summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot Applicable\nComments: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase - Autosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified. - Autosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.',0,''), -(808,23,'PS3','ACMG Summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\nNot Applicable\nComments: Protein: Do not use: Lack of known positive controls - RNA: Do not use: See code PVS1_Variable(RNA)',0,''), -(810,23,'PM1','ACMG Summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable\nComments: Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.',0,''), -(811,23,'PM2','ACMG Summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nVariant absent in gnomAD or present in <= 1/300,000 alleles\n\nInstructions:\n - PM2_supporting is not considered a conflicting piece of evidence for variants that otherwise are likely benign/benign \n - Use as PM2_Supporting (not moderate)',1,''), -(812,23,'PM3','ACMG Summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nGene-specific modifications:\nUse Fanconi Anemia PM3 tables (See instructions below)\n\nInstructions:\nFanconi Anemia (FA) of any subtype is generally considered an exceedingly rare, severe, early-onset disease with variable features. In the case of BRCA2, hypomorphic FA patients have been described who are diagnosed at older ages with less severe phenotypes. The criteria set forth in the tables below are designed to accommodate such hypomorphs and are recommended to be applied to all FA-associated genes which may not be as well described due to the extreme infrequency of their identification, and due to ascertainment bias (for severe phenotype) in the literature.\nVariant may not exceed general population frequency >0.01%. Consider other gene panel test results as potential explanation for phenotype. \nMultiple unrelated cases are additive. \n - Ex. one individual homozygous for a variant with Fanconi gets 2.0 points. Another individual affected with Fanconi Anemia has the same variant and another truncating PALB2 variant with phase unknown gets 2.0 points. In total, there are 4.0 points towards PM3.\nPhenotype consistent: Chromosomal breakage with 1 clinical feature OR at least 2 of 3 clinical features from separate categories without chromosomal breakage studies\n - Ex. Chromosomal breakage testing + microcephaly / triangular face \n - Ex. (Without chromosomal breakage): Myelodysplastic Syndrome and microcephaly / triangular face. Individuals must have features from at least 2 of 3 distinct Cinical Feature categories below. \n - Positive for chromosome breakage test:\n - Increased chromosome breakage and/or radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) or mitomycin C (MMC)\n - Clinical features indicative of FA, including \n - Physical features (in ~75% of affected persons), include: \n - prenatal and/or postnatal short stature\n - abnormal skin pigmentation (e.g., café au lait macules, hypo- pigmentation)\n - Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)\n - Microcephaly, triangular face\n - Ophthalmic anomalies\n - Genitourinary tract anomalies.\n - See Orphanet 13 for full list of >100 HPO terms (and their reported frequency).\n - Pathology findings and laboratory findings (non-cancer related) include\n - progressive bone marrow failure (unrelated to cancer treatment)\n - aplastic anemia\n - Myelodysplastic syndrome\n - Inordinate toxicities from chemotherapy or radiation\n - macrocytosis\n - cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)\n - increased fetal hemoglobin (often precedes anemia). \n - Note: FA patients with very early onset cancer (<=5yr) may not present with hematologic disease, which is reported to have median age at onset of 7 years in FA patients in general14\n - Cancer diagnosis <=5yr, particularly\n - Blood cancers (AML)\n - Brain cancers (medulloblastoma, neuroblastoma)\n - Wilms Tumor\n\nSpecifications are adapted from definitions from GeneReviews (last revision June 3, 2021)',1,''), -(813,23,'PM4','ACMG Summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: Do not use for in-frame deletions/insertions that are not already PVS1-eligible as no information is available to justify the application of this rule. - In addition, missense and small in-frame indels are not yet confirmed as a mechanism of disease for PALB2. - Do not use for stop-loss due to lack of data on stop-loss variants.',0,''), -(814,23,'PM5','ACMG Summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic, now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nApply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*\n\nInstructions:\n - For protein: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.\n - Apply as PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*\n - Apply to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Tyr1183 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone',1,''), -(815,23,'PM6','ACMG Summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable\nComments: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase',0,''), -(816,23,'PP1','ACMG Summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications:\n\nStrong: LOD >=1.26 or Bayes Factor (LR) >=18:1\nModerate: LOD >=.60 or Bayes Factor (LR) >=4:1\nSupporting: LOD >=0.3 or Bayes Factor (LR) >=2:1\n\nInstructions:\n - AD Condition: use as per Co-Segregation Guidelines\n - AR Condition: informative instances of co-segregation in FANCN families are too rare to be considered for weight at this time. \n - Co-Segregation Guidelines\n - Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores9 using multiple phenotypes.\n - PP1_Strong: LOD >=1.26 or Bayes Factor (LR) >=18:1\n - PP1_Moderate: LOD >=.60 or Bayes Factor (LR) >=4:1\n - PP1: LOD >=0.3 or Bayes Factor (LR) >=2:18\n - BS4_Supporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n - BS4_Moderate: LOD <= -.64 or Bayes Factor (LR) <=.23\n - BS4: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\n - A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng\'s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1. Navigate to COOL (COsegregation OnLine)\n 2. Input \'PALB2\' into the \'Input a Gene Symbol\' field (the PALB2 defaults are approved by this VCEP)\n 3. Upload your Pedigree File (see COOL (COsegregation OnLine) manual for formatting)\n 4. Leave all defaults as is. Select \'Submit\' to obtain LR based on Full Likelihood Bayes (FLB)',1,''), -(817,23,'PP2','ACMG Summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2',0,''), -(818,23,'PP3','ACMG Summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\n - Protein: Do not use.\n - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n\nInstructions:\n - Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants\n - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n - NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n - NOTE: PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes.\n - Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.',1,''), -(819,23,'PP4','ACMG Summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\nNot Applicable\nComments: Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. For AR disorder, use PM3 for specific phenotype considerations',0,''), -(820,23,'PP5','ACMG Summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(821,23,'BA1','ACMG Summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nGnomAD Filtering Allele Frequency Allele frequency >0.1%\n\nInstructions:\nRounded from .118% established using Whiffin calculator:\n - Prevalence (breast cancer): 1:8\n - Allelic Heterogeneity: 1 (differs from BS1)\n - Genetic Heterogeneity: .01\n - Penetrance: .53',1,''), -(822,23,'BS1','ACMG Summary:\nAllele frequency is greater than expected for disorder.\n\nGene-specific modifications:\nGnomAD Filtering Allele Frequency greater than expected for disease >.01%\n\nInstructions:\n - Rounded from .0118% established using Whiffin calculator: \n - Prevalence (breast cancer): 8 \n - Allelic Heterogeneity: 0.1 (differs from BA1) \n - Genetic Heterogeneity: .01 \n - Penetrance: .53',1,''), -(823,23,'BS2','ACMG Summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nPer Fanconi Anemia BS2 tables\n\nInstructions:\n See Fanconi Anemia BS2 tables\n Do not use for individuals in population based cohorts, such as gnomAD \n Consider multiple instances of co-occurrence with the same variant are more likely to be in cis in unrelated individuals when assessing BS2 application',1,''), -(824,23,'BS3','Original ACMG Summary\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\nNot Applicable\nComments: - Do not use: Protein functional studies (BS3) See PS3 for details - RNA functional studies (Use BP7_Variable(RNA))',0,''), -(825,23,'BS4','ACMG Summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nStrong: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\nModerate: LOD <= -.64 or Bayes Factor (LR) <=.23\nSupporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n\nInstructions:\n - Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores9 using multiple phenotypes. \n - PP1_Strong: LOD >=1.26 or Bayes Factor (LR) >=18:1 \n - PP1_Moderate: LOD >=.60 or Bayes Factor (LR) >=4:1\n - PP1: LOD >=0.3 or Bayes Factor (LR) >=2:1\n - BS4_Supporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n - BS4_Moderate: LOD <= -.64 or Bayes Factor (LR) <=.23\n - BS4: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\n - A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng\'s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1. Navigate to COOL (COsegregation OnLine)11\n 2. Input \'PALB2\' into the \'Input a Gene Symbol\' field (the PALB2 defaults are approved by this VCEP)\n 3. Upload your Pedigree File (see COOL (COsegregation OnLine) manual12 for formatting)\n 4. Leave all defaults as is. Select \'Submit\' to obtain LR based on Full Likelihood Bayes (FLB)',1,''), -(826,23,'BP1','ACMG Summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\n\nGene-specific modifications:\nApply to all missense variants.\n\nInstructions:\nBased on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2.',1,''), -(827,23,'BP2','ACMG Summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\nNot Applicable\nComments: Do not use: See Fanconi Anemia BS2 table',0,''), -(828,23,'BP3','ACMG Summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function',0,''), -(829,23,'BP4','ACMG Summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\nNot Applicable\nComments: - Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing o NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) o NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect) o Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.',0,''), -(830,23,'BP5','ACMG Summary:\nVariant found in a case with an alternate molecular basis for disease.\nNot Applicable\nComments: Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.',0,''), -(831,23,'BP6','ACMG Summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(832,23,'BP7','ACMG Summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nGene-specific modifications:\nStrong:\n - BP7_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality.\n\nModerate:\n - BP7_Variable(RNA):Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality\n\nSupporting:\n - BP7: Synonymous and deep intronic\n - BP7_Variable(RNA): Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality\n\nInstructions:\n - BP7: Synonymous and deep intronic\n - Can be used for deep intronic variants beyond (but not including) +7 (donor) and -21 (acceptor)\n - May also apply BP4 to achieve Likely Benign\n - Is not considered a conflicting piece of evidence against a body of evidence supporting a pathogenic splice defect\n - BP7_Variable(RNA): RNA functional studies\n - Lack of aberrant splice defect: Please see PVS1_Variable(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays\n - NOTE: BP4 splice predictions may not be used in conjunction with BP7',1,''), -(833,24,'PVS1','ACMG Summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nDefer to SVI recommendations',1,''), -(834,24,'PS1','ACMG Summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nStrong:\nMust confirm there is no difference in splicing using RNA data. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.\n\nModerate:\nMust confirm there is no difference in splicing using in silico modeling data using a splice metapredictor (SpliceAI, VarSEAK, etc). Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.\n\nInstructions:\nCan only compare to variants asserted as payhogenic by the ClinGen TP53 VCEP',1,''), -(835,24,'PS2','ACMG Summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\n\nGene-specific modifications:\nUse SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.\n\nVery Strong: ≥4 points (ex. - 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.\nStrong: 2-3 points (ex. - 1 cancer from the strong criteria list or 2 from the moderate criteria list)\nModerate: 1 point (for 1 cancer from the moderate criteria list)\nSupporting: 0.5 point (1 cancer from the moderate criteria list)\n\nInstructions:\nUse SVI point system table',1,''), -(836,24,'PS3','ACMG Summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\n\nGene-specific modifications:\nStrong:\nTransactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a low functioning allele (<= 20% activity) AND:\n Evidence of dominant negative effect (DNE) + evidence of LOF from Giacomelli, et al data OR\n There is a 2nd assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays) Do not use code with conflicting evidence\n\n\nModerate:\n(A) Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20-and <=75% activity) AND:\n Evidence of DNE + evidence of LOF from Giacomelli, et al data. OR\n There is a 2nd assay showing low function. Do not use code with conflicting evidence. (B) No transactivation assays (IARC classification based on data Kato et al, 2003) available BUT:\n Evidence of DNE + evidence of LOF from Giacomelli, et al data. AND\n There is a 2nd assay showing low function Do not use code with conflicting evidence.\n\nInstructions:\nSee flow chart for use of Kato, Giacomelli, and Kotler assays. Non-systematic assays are harder to interpret but if there are several of them and if all suggets benign or pathogenic, they should be taken into account. A large proportion of these assays are documented in the IARC database and should be easily found by curtators. Other assays that may be used including in vitro growth asaays in H1299 human cells from Kotler et al (2018) with RFS score >= -1.0 for LOF and RFS score <1 for noLOF, or colony formation assays, growth suppression assays, apoptosis assays, tetramer assays, knock-in mouse models. Do not use code with conflicting evidence.',1,''), -(837,24,'PS4','ACMG Summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nUse proband counting system described below in text.\n\nPS4 = 4+ points\nPS4_moderate = 2-3 points\nPS4_Suppporting = 1 point\n\nInstructions:\nUse proband counting system',1,''), -(838,24,'PM1','ACMG Summary\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\n\nGene-specific modifications:\nThis rule can be applied to variants in hot spots (codons 175, 245, 248, 249, 273, 282), but not to variants within functional domains. Use transcript NM_000546.4. Also use rule for variants with ≥10 somatic observations cancerhotspots.org (v2)',1,''), -(839,24,'PM2','ACMG Summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nVariant needs to be absent from controls. The variant must be absent from population databases. gnomAD is the preferred population database at this time (http://gnomad.broadinstitute.org). The most recent version of gnomAD with a non-cancer subpopulation should be used, however, other versions may be utilized if there is reason to believe they would provide necessary information for curating the variant.\nModification Type: Disease-specific,General recommendation\n\nInstructions:\nThe variant must be absent from population databases, gnomAD is the preferred pipulation database at this time.',1,''), -(840,24,'PM3','ACMG Summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\nNot Applicable\nComments: This rule does not apply to TP53/Li_Fraumeni syndrome.',0,''), -(841,24,'PM4','ACMG Summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: This rule should not be used at this time due to limited data.',0,''), -(842,24,'PM5','ACMG Summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic, now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nModerate:\nMultiple pathogenic variants (≥2) at that residue using the requirements specified below (excluding known hot spots) would be required. Grantham should be used to compare the variants. At least one of the new variants must be equal or worse than known pathogenic variant. Splicing should be ruled out. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP. Rule cannot be used in conjunction with PM1.\n\nSupporting:\nGrantham should be used to compare variants. The new variant must be equal or worse than known mutation. Splicing should be ruled out. Rule cannot be used in conjunction with PM1.\n\nInstructions:\nThis evidence code can be applied when there are >2 pathogenic variants at the same residue (excluding known hot spots). The other variants must be asserted as pathogenic by the ClinGen TP53 VCEP. Grantham should be used to compare the variants. The variant being evaluated must be equal to or worse than known mutations. Splicing should be ruled out.',1,''), -(843,24,'PM6','ACMG Summary:\nAssumed de novo, but without confirmation of paternity and maternity.\n\nGene-specific modifications:\nUse SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.\n\nVery Strong: ≥4 points (ex. - 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.\nStrong: 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)\nModerate: 1 point (for 1 cancer from the moderate criteria list)\nSupporting: 0.5 point (1 cancer from the moderate criteria list)\n\nInstructions:\nSee above for PS2_PM6 combined rule',1,''), -(844,24,'PP1','ACMG Summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications:\nCosegregation must be observed in...\nStrong: ≥7 meioses in >1 family\nModerate: 5-6 meioses in 1 family\nSupporting: 3-4 meioses in 1 family\nto apply this rule',1,''), -(845,24,'PP2','Original ACMG Summary\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: This rule does not apply due to the high number of benign missense variation.',0,''), -(846,24,'PP3','ACMG Summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nModerate:\nPolyPhen2 and SIFT in silico modeling programs should not be used for this gene. Missense variants: aGVGD (Zebrafish, Class C65 required) and BayesDel (score ≥ 0.16)\n\nSupporting:\nPolyPhen2 and SIFT in silico modeling programs should not be used for this gene. Concordance of two predictors is recommended for this gene:\n - Missense variants: aGVGD (Zebrafish, Class C25 and higher are considered evidence of pathogenicity) and BayesDel (scores ≥ 0.16 are considered evidence of pathogenic)\n - Splicing variants: Evidence of splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).\n\nInstructions:\nConcordance of two predictors is recommended for this gene. Missense variants: according to a published study by Fortuno et al 2018 comparing the performance of different bioinformatics tools for TP563, the tools selected are aGVGD (Zebrafish, Class C15 and higher are considered evidence of pathogenicity) and BayesDel (scores >=0.16 are considered evidence of pathogenic). Please refer to the cited manuscript for further details. Splicing variants: MaxEntScan and Human Splicing Finder (HSF) should be used.',1,''), -(847,24,'PP4','Original ACMG Summary\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\n\nGene-specific modifications:\nUse modified PS4 criteria instead of PP4 code.',1,''), -(848,24,'PP5','ACMG Summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(849,24,'BA1','ACMG Summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nFrequency cutoff of 0.1% minimum of 5 alleles present in the population\n\nInstructions:\nUse a minor allele frequency cutoff of >=0.001 or 0.1% (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on Wiffen-Ware calculator.',1,''), -(850,24,'BS1','ACMG Summary:\nAllele frequency is greater than expected for disorder.\n\nGene-specific modifications:\nFrequency cutoff of 0.03%, minimum of 5 alleles present in the population.\n - Use a minor allele frequency cutoff of >0.0003 but <0.001 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator.\n - To set the strong benign MAF cutoff, we used a prevalence of 1 in 5,000 from Lalloo, et a 2006 (PMID:16644204). We set the genetic and allelic heterogeneity at 100% and penetrance at 30%.\n\nInstructions:\nUse a minor allele frequency cutoff of >=0.0003 but <0.001 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on Whiffen-Ware calculator.',1,''), -(851,24,'BS2','ACMG Summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nStrong:\nObserved in ≥8 cancer free 60+ year old females obtained from the same data source. Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:\n - This evidence code can be used when a variant is observed in ≥8 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.\n\nSupporting:\nObserved in 2-7 cancer free 60+ year old females obtained from the same data source. Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:\n - This evidence code can be used when a variant is observed in 2-7 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.',1,''), -(852,24,'BS3','ACMG Summary:\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\n\nGene-specific modifications:\n\nStrong:\nTransactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that show retained function (76-140% activity) or supertransactivation function AND:\n - No evidence of DNE + no evidence of LOF from Giacomelli, et al data. OR There is a 2nd assay, including colony formation assays, apoptosis assays, tetramer assays, growth suppression and knock-in mouse models demonstrating retained function. Do not use code with conflicting evidence\n \nSupporting:\nTransactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <=75% activity) AND:\n-_No evidence of DNE + no evidence of LOF from Giacomelli, et al data. OR\n - There is a 2nd assay demonstrating retained function Do not use code with conflicting evidence. No transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) available BUT:\n - No evidence of DNE + no evidence of LOF from Giacomelli, et al data. AND There is a 2nd assay showing retained function Do not use code with conflicting evidence',1,''), -(853,24,'BS4','ACMG Summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nVariant segregates to opposite side of the family who meets LFS criteria. OR Variant is present in ≥3 living unaffected individuals (at least 2 of which should be female) above 55 years of age.\n\nInstructions:\nEvidence code can be used in either scenario: the variant segregates to the opposite side of the family who meets LFS criteria OR the variant is present in >=3 living unaffected individuals ( at least 2 of 3 should be female) above 55 years of age',1,''), -(854,24,'BP1','ACMG Summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\nNot Applicable\nComments: This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants.',0,''), -(855,24,'BP2','ACMG Summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\n\nGene-specific modifications:\nThis evidence code can be applied in either scenario below:\n - Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed), or\n - When there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two different pathogenic/likely pathogenic TP53 variants.\n\nInstructions:\nEvidence code can be applied in either scenario: Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed) OR when there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two differemt pathogenic or likely pathogenic TP53 variants.',1,''), -(856,24,'BP3','ACMG Summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Do not use this rule at this time.',0,''), -(857,24,'BP4','ACMG Summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nMissense: aGVGD (zebrafish, Class C0 or C15 is considered evidence of non-pathogenicity) and BayesDel <0.16 is considered evidence on non-pathogenicity Splicing: Evidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).\n\nInstructions:\nConcordance of two predictors is recommended for this gene. Missense variants: according to a published study by Fortuno et al 2018 comparing the performance of different bioinformatics tools for TP53, the tools selected are aGVGD (Zebrafish, Class C0 or C15 is considered evidence of non-pathogenicity_ and BayesDel <0.16 is considered evidence of non-pathogenicity). Splicing variants: MaxEntScan and Human Splicing Finder (HSF)',1,''), -(858,24,'BP5','ACMG Summary:\nVariant found in a case with an alternate molecular basis for disease.\nNot Applicable\nComments: This rule code is not recommended for use at this time.',0,''), -(859,24,'BP6','ACMG Summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(860,24,'BP7','ACMG Summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nGene-specific modifications:\nEvidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc). If a new alternate site is predicted, compare strength to native site in interpretation.\n\nInstructions:\nConcordance of MaxEntScan and Human Splice Finder are required to use this evidence code. If an alternate site is predicted, comapre strength to native site in interpretation',1,''), -(861,25,'PVS1','ACMG summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nNull variant (nonsense, frameshift, splice site (donor/acceptor +/-1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\nIn alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5_PTC code (See Appendix D for details).\nInstructions:\nSee Specifications Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the BRCA1 and BRCA2 PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor +/- 1,2)) - organized by exon. See Appendix Figure 3,4 and Table 5 for further justification.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.',1,''), -(862,25,'PS1','ACMG summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nStrong:\nApply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1, for exonic and intronic variants with same predicted impact on splicing, as a previously classified pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \nSee Specifications Table 5 and Appendix E, J and K for details.\n\nModerate:\nApply PS1_Moderate, for predicted missense substitutions, where previously classified likely pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1_Moderate, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\nSupporting:\nApply PS1_Supporting, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\nInstructions:\nFor both missense and splicing scenarios, (Likely) Pathogenic variant classification should be assigned using VCEP specifications.\nFor application of PS1 for splicing predictions, see Specifications Table 5. The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the variant and the previously classified pathogenic variant should also be considered before PS1 code application for splicing prediction.',1,''), -(863,25,'PS2','ACMG summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''), -(864,25,'PS3','ACMG summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''), -(865,25,'PS4','ACMG summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies, p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.\nModification Type: Clarification,Gene-specific\n\nInstructions:\nCase dataset should be ethnicity and country-matched to control dataset. If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). Do not use Proband Counting as originally described.',1,''), -(866,25,'PM1','ACMG summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''), -(867,25,'PM2','ACMG summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-Specific modifications:\nAbsent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.\nModification Type: Gene-specific\n\nInstructions:\nObservation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth <25 at region around the variant.',1,''), -(868,25,'PM3','ACMG summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nApply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3_Strong = ≥4 points\nPM3 = 2 points\nPM3_Supporting = 1 point\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nVariant under assessment must be sufficiently rare (meet PM2_Supporting, or PM2 not applicable).\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\nFor related individuals score only most severe presentation.\nAlso see Specifications Table 6 for additional stipulations',1,''), -(869,25,'PM4','ACMG summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''), -(870,25,'PM5','ACMG summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic, now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nProtein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.\n\nInstructions:\nOnly applied to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). See Specifications Table 4, provided as a separate searchable excel file, for PM5_PTC codes applicable for predicted termination codon variants - organized by exon.',1,''), -(871,25,'PM6','ACMG summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''), -(872,25,'PP1','ACMG summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\nPP1_Very Strong - LR>350:1\nPP1_Strong - LR>18.7:1\nPP1_Moderate - LR>4.3:1\nPP1 - LR >2.08:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.\nStipulation: to apply code as Pathogenic Very Strong, VUS should have bioinformatically predicted (or experimentally proven) effect on protein or mRNA splicing. If co-segregation score is from a single family, or several families from an isolated population, assess the possibility of a different causative pathogenic variant.',1,''), -(873,25,'PP2','ACMG summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: High frequency of benign missense variants.',0,''), -(874,25,'PP3','ACMG summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nApply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857.\nApply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.\nSee Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''), -(875,25,'PP4','ACMG summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\n\nGene-specific modifications:\nBreast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4_Very Strong - LR>350:1\nPP4_Strong - LR>18.7:1\nPP4_Moderate - LR>4.3:1\nPP4 - LR >2.08:1 \nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\nSee Specifications Table7 and Appendix B for details.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''), -(876,25,'PP5','ACMG summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(877,25,'BA1','ACMG summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nFilter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''), -(878,25,'BS1','ACMG summary:\nAllele frequency is greater than expected for disorder.\n\nStrong:\nFilter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nSupporting:\nFilter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''), -(879,25,'BS2','ACMG summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nApplied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See Specifications Table 8 for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2 = ≥ 4 points\nBS2_Moderate = 2 points\nBS2_Supporting = 1 points\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nSee Specifications Table 8 for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\nAlso see Specifications Table 8 for additional stipulations.',1,''), -(880,25,'BS3','ACMG summary:\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of no damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''), -(881,25,'BS4','ACMG summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nLack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\nBS4_VeryStrong - LR <0.00285:1\nBS4 - LR <0.05:1\nBS4_Moderate - LR <0.23:1\nBS4_Supporting - LR 0.23-0.48:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.',1,''), -(882,25,'BP1','ACMG summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\n\nGene-specific modifications:\nApply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact. Missense prediction not applicable.',1,''), -(883,25,'BP2','ACMG summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\nNot Applicable\nComments: Applied only in the context of BS2.',0,''), -(884,25,'BP3','ACMG summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details',0,''), -(885,25,'BP4','ACMG summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nMissense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.15 AND SpliceAI ≤0.1).\nSilent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).\nIntronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''), -(886,25,'BP5','ACMG summary:\nVariant found in a case with an alternate molecular basis for disease.\n\nGene-specific modifications:\nUse ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5_VeryStrong - LR <0.00285:1\nBP5_Strong - LR <0.05:1\nBP5_Moderate - LR <0.23:1\nBP5 - LR 0.23-0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast-ovarian cancer risk genes have no specific phenotype.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''), -(887,25,'BP6','ACMG summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(888,25,'BP7','ACMG summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nStrong:\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile - mRNA assay only. Apply as BP7 (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nSupporting:\nSilent variant inside a (potentially) clinically important functional domain, IF BP4 met.\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\nSee Specifications Figure1A and Appendix J for additional details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101, BRCA1 coiled-coil aa 1391-1424, BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained. Not applicable for missense variants inside a (potentially) clinically important functional domain as they may still impact protein function through the amino acid change.\nFollowing convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI ≤0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. See Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''), -(889,26,'PVS1','ACMG Summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nInstructions:\n - Use PALB2 PVS1 Decision Tree Per PALB2 Exon Map and PALB2 PVS1 Guide \n - PVS1: Predicted splice defect \n - PVS1_Strength(RNA): Observed splice defect \n - The default RefSeq transcript for nucleotide (c.) annotation is NM_024675.3/ENST00000261584.8. Several naturally occurring alternate splicing isoforms have been described. Yet, after careful examination, none of them is considered a candidate rescue transcript (very low contribution to overall expression, not coding proteins predicted functional, or both). In keeping with that, we have considered that all presumed LoF events (PVS1 decision tree specifications) occur in biologically relevant transcript(s).\n - WD40 beta propeller and the Coiled-coil domain (CC) are considered indispensable for PALB2 protein function. \n - PVS1 alterations that are predicted to escape NMD, but that adversely affect the WD40 domain can be granted PVS1 (as opposed to PVS1_Strong as the recommended baseline. The following evidence supports this strength change: \n - The WD40 domain interacts with many different protein partners that are involved in the double strand break repair pathway3\n - Two different C-terminal truncating mutations (c.3549C>A and c.3549C>G) resulting in loss of the last 3 amino acids [p.(Tyr1183Ter)], were identified in trans with PALB2 stop-gain variants in three unrelated FA (FA-N) patients4\n - The PALB2 WD40 toroidal structure is “sealed” in the seventh blade by interaction of the C-terminal strand with the incomplete N-terminal blade. The last four residues of PALB2 (Y1183, H1184, Y1185, and S1186) are directly involved in this interaction (molecular Velcro hydrogen bonding)00. This is the rationale for the clinical relevance of the last 4 amino acids of the protein.\n - Alterations predicted to lead to in frame losses adversely affecting the WD40 structure/function are found in trans with LoF PALB2 alterations in Fanconi Anemia patients4\n - Exon 10 donor: c.3113+5G>C (biallelic with c.395delT)\n - Exon 12 donor: c.3350+4A>G (biallelic with c.2393_2394insCT)\n - LoF alterations are rare in GnomAD in all exons\n - GnomAD v2.1 accessed 5/30/2019\n - Total Variants (includes splice acceptor/donor-conservative)\n - 1418 variants\n - 336,349 carriers\n - LoF Flag (excludes splice acceptor/donor-conservative)\n - 95 variants (6.7%)\n - 239 carriers (.07%)\n - PVS1 can be applied as per the PVS1 decision tree.\n - PVS1_Variable(RNA) shall be used for observed splice defects, whether from canonical +/-1,2 positions or other spliceogenic regions (including mid-exonic missense/synonymous variants that cause splice defects) with baseline weight as per the below decision tree. Weight can be further modified based on the quality of the RNA study including consideration of concepts such as:\n - Starting material (where patient material is preferable to in vitro minigene)\n - Use of NMD inhibitors where translation does occur such as cell lines56\n - Primer design (to make sure it\'s comprehensive to capture possible multicassette events)\n - Method of quantification \n - where e.g. capillary electrophoresis is preferable to estimation by gel band density\n - where SNP analysis is most preferred (where analysis of exonic SNPs and their relative presence in aberrant and WT transcripts is informative)\n - Quantification (where complete effects should have increased weight over incomplete effects)\n - Specific guidance on the use of RNA evidence in variant assessment is not a gene-specific consideration for PALB2 at this time, therefore discretion is left to assessors until further guidance is provided for this general concept from the Sequence Variant Interpretation group.',1,''), -(890,26,'PS1','ACMG Summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nCase-control studies, p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=3 OR lower 95% CI >=1.5).\n\nInstructions:\nPS4_Moderate: Do not use. Proband counting for genes causing a common disorder need to be calibrated in a population-specific way before use.',1,''), -(891,26,'PS2','ACMG Summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot Applicable\nComments: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase - Autosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified. - Autosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.',0,''), -(892,26,'PS3','ACMG Summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\nNot Applicable\nComments: Protein: Do not use: Lack of known positive controls - RNA: Do not use: See code PVS1_Variable(RNA)',0,''), -(894,26,'PM1','ACMG Summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable\nComments: Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.',0,''), -(895,26,'PM2','ACMG Summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nVariant absent in gnomAD or present in <= 1/300,000 alleles\n\nInstructions:\n - PM2_supporting is not considered a conflicting piece of evidence for variants that otherwise are likely benign/benign \n - Use as PM2_Supporting (not moderate)',1,''), -(896,26,'PM3','ACMG Summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nGene-specific modifications:\nUse Fanconi Anemia PM3 tables (See instructions below)\n\nInstructions:\nFanconi Anemia (FA) of any subtype is generally considered an exceedingly rare, severe, early-onset disease with variable features. In the case of BRCA2, hypomorphic FA patients have been described who are diagnosed at older ages with less severe phenotypes. The criteria set forth in the tables below are designed to accommodate such hypomorphs and are recommended to be applied to all FA-associated genes which may not be as well described due to the extreme infrequency of their identification, and due to ascertainment bias (for severe phenotype) in the literature.\nVariant may not exceed general population frequency >0.01%. Consider other gene panel test results as potential explanation for phenotype. \nMultiple unrelated cases are additive. \n - Ex. one individual homozygous for a variant with Fanconi gets 2.0 points. Another individual affected with Fanconi Anemia has the same variant and another truncating PALB2 variant with phase unknown gets 2.0 points. In total, there are 4.0 points towards PM3.\nPhenotype consistent: Chromosomal breakage with 1 clinical feature OR at least 2 of 3 clinical features from separate categories without chromosomal breakage studies\n - Ex. Chromosomal breakage testing + microcephaly / triangular face \n - Ex. (Without chromosomal breakage): Myelodysplastic Syndrome and microcephaly / triangular face. Individuals must have features from at least 2 of 3 distinct Cinical Feature categories below. \n - Positive for chromosome breakage test:\n - Increased chromosome breakage and/or radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) or mitomycin C (MMC)\n - Clinical features indicative of FA, including \n - Physical features (in ~75% of affected persons), include: \n - prenatal and/or postnatal short stature\n - abnormal skin pigmentation (e.g., café au lait macules, hypo- pigmentation)\n - Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)\n - Microcephaly, triangular face\n - Ophthalmic anomalies\n - Genitourinary tract anomalies.\n - See Orphanet 13 for full list of >100 HPO terms (and their reported frequency).\n - Pathology findings and laboratory findings (non-cancer related) include\n - progressive bone marrow failure (unrelated to cancer treatment)\n - aplastic anemia\n - Myelodysplastic syndrome\n - Inordinate toxicities from chemotherapy or radiation\n - macrocytosis\n - cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)\n - increased fetal hemoglobin (often precedes anemia). \n - Note: FA patients with very early onset cancer (<=5yr) may not present with hematologic disease, which is reported to have median age at onset of 7 years in FA patients in general14\n - Cancer diagnosis <=5yr, particularly\n - Blood cancers (AML)\n - Brain cancers (medulloblastoma, neuroblastoma)\n - Wilms Tumor\n\nSpecifications are adapted from definitions from GeneReviews (last revision June 3, 2021)',1,''), -(897,26,'PM4','ACMG Summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: Do not use for in-frame deletions/insertions that are not already PVS1-eligible as no information is available to justify the application of this rule. - In addition, missense and small in-frame indels are not yet confirmed as a mechanism of disease for PALB2. - Do not use for stop-loss due to lack of data on stop-loss variants.',0,''), -(898,26,'PM5','ACMG Summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic, now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nApply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*\n\nInstructions:\n - For protein: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.\n - Apply as PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*\n - Apply to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Tyr1183 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone',1,''), -(899,26,'PM6','ACMG Summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable\nComments: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase',0,''), -(900,26,'PP1','ACMG Summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications:\n\nStrong: LOD >=1.26 or Bayes Factor (LR) >=18:1\nModerate: LOD >=.60 or Bayes Factor (LR) >=4:1\nSupporting: LOD >=0.3 or Bayes Factor (LR) >=2:1\n\nInstructions:\n - AD Condition: use as per Co-Segregation Guidelines\n - AR Condition: informative instances of co-segregation in FANCN families are too rare to be considered for weight at this time. \n - Co-Segregation Guidelines\n - Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores9 using multiple phenotypes.\n - PP1_Strong: LOD >=1.26 or Bayes Factor (LR) >=18:1\n - PP1_Moderate: LOD >=.60 or Bayes Factor (LR) >=4:1\n - PP1: LOD >=0.3 or Bayes Factor (LR) >=2:18\n - BS4_Supporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n - BS4_Moderate: LOD <= -.64 or Bayes Factor (LR) <=.23\n - BS4: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\n - A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng\'s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1. Navigate to COOL (COsegregation OnLine)\n 2. Input \'PALB2\' into the \'Input a Gene Symbol\' field (the PALB2 defaults are approved by this VCEP)\n 3. Upload your Pedigree File (see COOL (COsegregation OnLine) manual for formatting)\n 4. Leave all defaults as is. Select \'Submit\' to obtain LR based on Full Likelihood Bayes (FLB)',1,''), -(901,26,'PP2','ACMG Summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2',0,''), -(902,26,'PP3','ACMG Summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\n - Protein: Do not use.\n - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n\nInstructions:\n - Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants\n - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n - NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n - NOTE: PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes.\n - Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.',1,''), -(903,26,'PP4','ACMG Summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\nNot Applicable\nComments: Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. For AR disorder, use PM3 for specific phenotype considerations',0,''), -(904,26,'PP5','ACMG Summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(905,26,'BA1','ACMG Summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nGnomAD Filtering Allele Frequency Allele frequency >0.1%\n\nInstructions:\nRounded from .118% established using Whiffin calculator:\n - Prevalence (breast cancer): 1:8\n - Allelic Heterogeneity: 1 (differs from BS1)\n - Genetic Heterogeneity: .01\n - Penetrance: .53',1,''), -(906,26,'BS1','ACMG Summary:\nAllele frequency is greater than expected for disorder.\n\nGene-specific modifications:\nGnomAD Filtering Allele Frequency greater than expected for disease >.01%\n\nInstructions:\n - Rounded from .0118% established using Whiffin calculator: \n - Prevalence (breast cancer): 8 \n - Allelic Heterogeneity: 0.1 (differs from BA1) \n - Genetic Heterogeneity: .01 \n - Penetrance: .53',1,''), -(907,26,'BS2','ACMG Summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nPer Fanconi Anemia BS2 tables\n\nInstructions:\n See Fanconi Anemia BS2 tables\n Do not use for individuals in population based cohorts, such as gnomAD \n Consider multiple instances of co-occurrence with the same variant are more likely to be in cis in unrelated individuals when assessing BS2 application',1,''), -(908,26,'BS3','Original ACMG Summary\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\nNot Applicable\nComments: - Do not use: Protein functional studies (BS3) See PS3 for details - RNA functional studies (Use BP7_Variable(RNA))',0,''), -(909,26,'BS4','ACMG Summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nStrong: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\nModerate: LOD <= -.64 or Bayes Factor (LR) <=.23\nSupporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n\nInstructions:\n - Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores9 using multiple phenotypes. \n - PP1_Strong: LOD >=1.26 or Bayes Factor (LR) >=18:1 \n - PP1_Moderate: LOD >=.60 or Bayes Factor (LR) >=4:1\n - PP1: LOD >=0.3 or Bayes Factor (LR) >=2:1\n - BS4_Supporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n - BS4_Moderate: LOD <= -.64 or Bayes Factor (LR) <=.23\n - BS4: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\n - A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng\'s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1. Navigate to COOL (COsegregation OnLine)11\n 2. Input \'PALB2\' into the \'Input a Gene Symbol\' field (the PALB2 defaults are approved by this VCEP)\n 3. Upload your Pedigree File (see COOL (COsegregation OnLine) manual12 for formatting)\n 4. Leave all defaults as is. Select \'Submit\' to obtain LR based on Full Likelihood Bayes (FLB)',1,''), -(910,26,'BP1','ACMG Summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\n\nGene-specific modifications:\nApply to all missense variants.\n\nInstructions:\nBased on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2.',1,''), -(911,26,'BP2','ACMG Summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\nNot Applicable\nComments: Do not use: See Fanconi Anemia BS2 table',0,''), -(912,26,'BP3','ACMG Summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function',0,''), -(913,26,'BP4','ACMG Summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\nNot Applicable\nComments: - Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing o NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) o NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect) o Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.',0,''), -(914,26,'BP5','ACMG Summary:\nVariant found in a case with an alternate molecular basis for disease.\nNot Applicable\nComments: Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.',0,''), -(915,26,'BP6','ACMG Summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(916,26,'BP7','ACMG Summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nGene-specific modifications:\nStrong:\n - BP7_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality.\n\nModerate:\n - BP7_Variable(RNA):Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality\n\nSupporting:\n - BP7: Synonymous and deep intronic\n - BP7_Variable(RNA): Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality\n\nInstructions:\n - BP7: Synonymous and deep intronic\n - Can be used for deep intronic variants beyond (but not including) +7 (donor) and -21 (acceptor)\n - May also apply BP4 to achieve Likely Benign\n - Is not considered a conflicting piece of evidence against a body of evidence supporting a pathogenic splice defect\n - BP7_Variable(RNA): RNA functional studies\n - Lack of aberrant splice defect: Please see PVS1_Variable(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays\n - NOTE: BP4 splice predictions may not be used in conjunction with BP7',1,''), -(917,27,'PVS1','ACMG Summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nInstructions:\n - Use PALB2 PVS1 Decision Tree Per PALB2 Exon Map and PALB2 PVS1 Guide \n - PVS1: Predicted splice defect \n - PVS1_Strength(RNA): Observed splice defect \n - The default RefSeq transcript for nucleotide (c.) annotation is NM_024675.3/ENST00000261584.8. Several naturally occurring alternate splicing isoforms have been described. Yet, after careful examination, none of them is considered a candidate rescue transcript (very low contribution to overall expression, not coding proteins predicted functional, or both). In keeping with that, we have considered that all presumed LoF events (PVS1 decision tree specifications) occur in biologically relevant transcript(s).\n - WD40 beta propeller and the Coiled-coil domain (CC) are considered indispensable for PALB2 protein function. \n - PVS1 alterations that are predicted to escape NMD, but that adversely affect the WD40 domain can be granted PVS1 (as opposed to PVS1_Strong as the recommended baseline. The following evidence supports this strength change: \n - The WD40 domain interacts with many different protein partners that are involved in the double strand break repair pathway3\n - Two different C-terminal truncating mutations (c.3549C>A and c.3549C>G) resulting in loss of the last 3 amino acids [p.(Tyr1183Ter)], were identified in trans with PALB2 stop-gain variants in three unrelated FA (FA-N) patients4\n - The PALB2 WD40 toroidal structure is “sealed” in the seventh blade by interaction of the C-terminal strand with the incomplete N-terminal blade. The last four residues of PALB2 (Y1183, H1184, Y1185, and S1186) are directly involved in this interaction (molecular Velcro hydrogen bonding)00. This is the rationale for the clinical relevance of the last 4 amino acids of the protein.\n - Alterations predicted to lead to in frame losses adversely affecting the WD40 structure/function are found in trans with LoF PALB2 alterations in Fanconi Anemia patients4\n - Exon 10 donor: c.3113+5G>C (biallelic with c.395delT)\n - Exon 12 donor: c.3350+4A>G (biallelic with c.2393_2394insCT)\n - LoF alterations are rare in GnomAD in all exons\n - GnomAD v2.1 accessed 5/30/2019\n - Total Variants (includes splice acceptor/donor-conservative)\n - 1418 variants\n - 336,349 carriers\n - LoF Flag (excludes splice acceptor/donor-conservative)\n - 95 variants (6.7%)\n - 239 carriers (.07%)\n - PVS1 can be applied as per the PVS1 decision tree.\n - PVS1_Variable(RNA) shall be used for observed splice defects, whether from canonical +/-1,2 positions or other spliceogenic regions (including mid-exonic missense/synonymous variants that cause splice defects) with baseline weight as per the below decision tree. Weight can be further modified based on the quality of the RNA study including consideration of concepts such as:\n - Starting material (where patient material is preferable to in vitro minigene)\n - Use of NMD inhibitors where translation does occur such as cell lines56\n - Primer design (to make sure it\'s comprehensive to capture possible multicassette events)\n - Method of quantification \n - where e.g. capillary electrophoresis is preferable to estimation by gel band density\n - where SNP analysis is most preferred (where analysis of exonic SNPs and their relative presence in aberrant and WT transcripts is informative)\n - Quantification (where complete effects should have increased weight over incomplete effects)\n - Specific guidance on the use of RNA evidence in variant assessment is not a gene-specific consideration for PALB2 at this time, therefore discretion is left to assessors until further guidance is provided for this general concept from the Sequence Variant Interpretation group.',1,''), -(918,27,'PS1','ACMG Summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nCase-control studies, p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=3 OR lower 95% CI >=1.5).\n\nInstructions:\nPS4_Moderate: Do not use. Proband counting for genes causing a common disorder need to be calibrated in a population-specific way before use.',1,''), -(919,27,'PS2','ACMG Summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot Applicable\nComments: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase - Autosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified. - Autosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.',0,''), -(920,27,'PS3','ACMG Summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\nNot Applicable\nComments: Protein: Do not use: Lack of known positive controls - RNA: Do not use: See code PVS1_Variable(RNA)',0,''), -(922,27,'PM1','ACMG Summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable\nComments: Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.',0,''), -(923,27,'PM2','ACMG Summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nVariant absent in gnomAD or present in <= 1/300,000 alleles\n\nInstructions:\n - PM2_supporting is not considered a conflicting piece of evidence for variants that otherwise are likely benign/benign \n - Use as PM2_Supporting (not moderate)',1,''), -(924,27,'PM3','ACMG Summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nGene-specific modifications:\nUse Fanconi Anemia PM3 tables (See instructions below)\n\nInstructions:\nFanconi Anemia (FA) of any subtype is generally considered an exceedingly rare, severe, early-onset disease with variable features. In the case of BRCA2, hypomorphic FA patients have been described who are diagnosed at older ages with less severe phenotypes. The criteria set forth in the tables below are designed to accommodate such hypomorphs and are recommended to be applied to all FA-associated genes which may not be as well described due to the extreme infrequency of their identification, and due to ascertainment bias (for severe phenotype) in the literature.\nVariant may not exceed general population frequency >0.01%. Consider other gene panel test results as potential explanation for phenotype. \nMultiple unrelated cases are additive. \n - Ex. one individual homozygous for a variant with Fanconi gets 2.0 points. Another individual affected with Fanconi Anemia has the same variant and another truncating PALB2 variant with phase unknown gets 2.0 points. In total, there are 4.0 points towards PM3.\nPhenotype consistent: Chromosomal breakage with 1 clinical feature OR at least 2 of 3 clinical features from separate categories without chromosomal breakage studies\n - Ex. Chromosomal breakage testing + microcephaly / triangular face \n - Ex. (Without chromosomal breakage): Myelodysplastic Syndrome and microcephaly / triangular face. Individuals must have features from at least 2 of 3 distinct Cinical Feature categories below. \n - Positive for chromosome breakage test:\n - Increased chromosome breakage and/or radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) or mitomycin C (MMC)\n - Clinical features indicative of FA, including \n - Physical features (in ~75% of affected persons), include: \n - prenatal and/or postnatal short stature\n - abnormal skin pigmentation (e.g., café au lait macules, hypo- pigmentation)\n - Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)\n - Microcephaly, triangular face\n - Ophthalmic anomalies\n - Genitourinary tract anomalies.\n - See Orphanet 13 for full list of >100 HPO terms (and their reported frequency).\n - Pathology findings and laboratory findings (non-cancer related) include\n - progressive bone marrow failure (unrelated to cancer treatment)\n - aplastic anemia\n - Myelodysplastic syndrome\n - Inordinate toxicities from chemotherapy or radiation\n - macrocytosis\n - cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)\n - increased fetal hemoglobin (often precedes anemia). \n - Note: FA patients with very early onset cancer (<=5yr) may not present with hematologic disease, which is reported to have median age at onset of 7 years in FA patients in general14\n - Cancer diagnosis <=5yr, particularly\n - Blood cancers (AML)\n - Brain cancers (medulloblastoma, neuroblastoma)\n - Wilms Tumor\n\nSpecifications are adapted from definitions from GeneReviews (last revision June 3, 2021)',1,''), -(925,27,'PM4','ACMG Summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: Do not use for in-frame deletions/insertions that are not already PVS1-eligible as no information is available to justify the application of this rule. - In addition, missense and small in-frame indels are not yet confirmed as a mechanism of disease for PALB2. - Do not use for stop-loss due to lack of data on stop-loss variants.',0,''), -(926,27,'PM5','ACMG Summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic, now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nApply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*\n\nInstructions:\n - For protein: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.\n - Apply as PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*\n - Apply to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Tyr1183 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone',1,''), -(927,27,'PM6','ACMG Summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable\nComments: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase',0,''), -(928,27,'PP1','ACMG Summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications:\n\nStrong: LOD >=1.26 or Bayes Factor (LR) >=18:1\nModerate: LOD >=.60 or Bayes Factor (LR) >=4:1\nSupporting: LOD >=0.3 or Bayes Factor (LR) >=2:1\n\nInstructions:\n - AD Condition: use as per Co-Segregation Guidelines\n - AR Condition: informative instances of co-segregation in FANCN families are too rare to be considered for weight at this time. \n - Co-Segregation Guidelines\n - Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores9 using multiple phenotypes.\n - PP1_Strong: LOD >=1.26 or Bayes Factor (LR) >=18:1\n - PP1_Moderate: LOD >=.60 or Bayes Factor (LR) >=4:1\n - PP1: LOD >=0.3 or Bayes Factor (LR) >=2:18\n - BS4_Supporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n - BS4_Moderate: LOD <= -.64 or Bayes Factor (LR) <=.23\n - BS4: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\n - A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng\'s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1. Navigate to COOL (COsegregation OnLine)\n 2. Input \'PALB2\' into the \'Input a Gene Symbol\' field (the PALB2 defaults are approved by this VCEP)\n 3. Upload your Pedigree File (see COOL (COsegregation OnLine) manual for formatting)\n 4. Leave all defaults as is. Select \'Submit\' to obtain LR based on Full Likelihood Bayes (FLB)',1,''), -(929,27,'PP2','ACMG Summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2',0,''), -(930,27,'PP3','ACMG Summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\n - Protein: Do not use.\n - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n\nInstructions:\n - Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants\n - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n - NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n - NOTE: PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes.\n - Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.',1,''), -(931,27,'PP4','ACMG Summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\nNot Applicable\nComments: Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. For AR disorder, use PM3 for specific phenotype considerations',0,''), -(932,27,'PP5','ACMG Summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(933,27,'BA1','ACMG Summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nGnomAD Filtering Allele Frequency Allele frequency >0.1%\n\nInstructions:\nRounded from .118% established using Whiffin calculator:\n - Prevalence (breast cancer): 1:8\n - Allelic Heterogeneity: 1 (differs from BS1)\n - Genetic Heterogeneity: .01\n - Penetrance: .53',1,''), -(934,27,'BS1','ACMG Summary:\nAllele frequency is greater than expected for disorder.\n\nGene-specific modifications:\nGnomAD Filtering Allele Frequency greater than expected for disease >.01%\n\nInstructions:\n - Rounded from .0118% established using Whiffin calculator: \n - Prevalence (breast cancer): 8 \n - Allelic Heterogeneity: 0.1 (differs from BA1) \n - Genetic Heterogeneity: .01 \n - Penetrance: .53',1,''), -(935,27,'BS2','ACMG Summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nPer Fanconi Anemia BS2 tables\n\nInstructions:\n See Fanconi Anemia BS2 tables\n Do not use for individuals in population based cohorts, such as gnomAD \n Consider multiple instances of co-occurrence with the same variant are more likely to be in cis in unrelated individuals when assessing BS2 application',1,''), -(936,27,'BS3','Original ACMG Summary\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\nNot Applicable\nComments: - Do not use: Protein functional studies (BS3) See PS3 for details - RNA functional studies (Use BP7_Variable(RNA))',0,''), -(937,27,'BS4','ACMG Summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nStrong: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\nModerate: LOD <= -.64 or Bayes Factor (LR) <=.23\nSupporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n\nInstructions:\n - Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores9 using multiple phenotypes. \n - PP1_Strong: LOD >=1.26 or Bayes Factor (LR) >=18:1 \n - PP1_Moderate: LOD >=.60 or Bayes Factor (LR) >=4:1\n - PP1: LOD >=0.3 or Bayes Factor (LR) >=2:1\n - BS4_Supporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n - BS4_Moderate: LOD <= -.64 or Bayes Factor (LR) <=.23\n - BS4: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\n - A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng\'s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1. Navigate to COOL (COsegregation OnLine)11\n 2. Input \'PALB2\' into the \'Input a Gene Symbol\' field (the PALB2 defaults are approved by this VCEP)\n 3. Upload your Pedigree File (see COOL (COsegregation OnLine) manual12 for formatting)\n 4. Leave all defaults as is. Select \'Submit\' to obtain LR based on Full Likelihood Bayes (FLB)',1,''), -(938,27,'BP1','ACMG Summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\n\nGene-specific modifications:\nApply to all missense variants.\n\nInstructions:\nBased on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2.',1,''), -(939,27,'BP2','ACMG Summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\nNot Applicable\nComments: Do not use: See Fanconi Anemia BS2 table',0,''), -(940,27,'BP3','ACMG Summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function',0,''), -(941,27,'BP4','ACMG Summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\nNot Applicable\nComments: - Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing o NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) o NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect) o Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.',0,''), -(942,27,'BP5','ACMG Summary:\nVariant found in a case with an alternate molecular basis for disease.\nNot Applicable\nComments: Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.',0,''), -(943,27,'BP6','ACMG Summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''), -(944,27,'BP7','ACMG Summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nGene-specific modifications:\nStrong:\n - BP7_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality.\n\nModerate:\n - BP7_Variable(RNA):Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality\n\nSupporting:\n - BP7: Synonymous and deep intronic\n - BP7_Variable(RNA): Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality\n\nInstructions:\n - BP7: Synonymous and deep intronic\n - Can be used for deep intronic variants beyond (but not including) +7 (donor) and -21 (acceptor)\n - May also apply BP4 to achieve Likely Benign\n - Is not considered a conflicting piece of evidence against a body of evidence supporting a pathogenic splice defect\n - BP7_Variable(RNA): RNA functional studies\n - Lack of aberrant splice defect: Please see PVS1_Variable(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays\n - NOTE: BP4 splice predictions may not be used in conjunction with BP7',1,''), -(1089,23,'PS4','ACMG Summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nCase-control studies, p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=3 OR lower 95% CI >=1.5).\n\nInstructions:\nPS4_Moderate: Do not use. Proband counting for genes causing a common disorder need to be calibrated in a population-specific way before use.',1,''), -(1281,28,'PVS1','Original ACMG Summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nUse ATM PVS1 Decision Tree.',1,''), -(1282,28,'PS1','Original ACMG Summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nStrong:\nUse for protein changes as long as splicing is ruled-out for both alterations.\n\nModerate:\nUse for RNA changes as code PS1_RNA_Moderate if predictions or observations are similar or worse for the variant under consideration. Close matches must be VCEP approved LP/P variants.\n\nInstructions:\nUse as ascribed for protein changes as long as a splice defect is ruled out for both variants, Use as PS1_RNA_Moderate for close-match splicing variants with similar predictions or observations of splice defect. Close matches must be VCEP approved as LP/P.',1,''), -(1283,28,'PS2','Original ACMG Summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot Applicable',0,''), -(1284,28,'PS3','Original ACMG Summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\n\nGene-specific modifications:\nStrong:\nDo not use as strong.\n\nModerate:\nUse when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.\n\nSupporting:\nUse when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency\n\nInstructions:\nFor protein, see detailed notes on ATM-specific assays, For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion).',1,''), -(1285,28,'PS4','Original ACMG Summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nStrong:\nUse for case control studies that reflect an OR ≥2, p≤.05 and lower 95% CI ≥1.5.\n\nModerate:\nDo not use for proband counting.\n\nInstructions:\nDo not use for \'proband counting\' method. Use for case control studies that reflect an OR ≥2, p≤.05 and lower 95% CI ≥1.5.',1,''), -(1286,28,'PM1','Original ACMG Summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable',0,''), -(1287,28,'PM2','Original ACMG Summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nFrequency ≤.001% when N>1 in a large general population database (e.g. gnomAD 2.1.1)\n\nInstructions:\nUse as PM2_Supporting for variants with a general population frequency ≤.001% in all sub-populations when N>1.',1,''), -(1288,28,'PM3','Original ACMG Summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nInstructions:\nUse ATM PM3/BP2 table.',1,''), -(1289,28,'PM4','Original ACMG Summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\nGene-specific modifications:\nUse for stop-loss variants.\n\nInstructions:\nDo not use for in-frame insertions or deletions less than a single exon, Use for stop-loss variants, only.',1,''), -(1290,28,'PM5','Original ACMG Summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic, now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nUse for genomic frameshift and truncating variants with PTC upstream of p.R3047. Do not use for splice or start-loss variants\n\nInstructions:\nDo not use for \'hotspot\'. Can be used for genomic frameshift and truncating variants with PTC upstream of p.R3047 as PM5_Supporting.',1,''), -(1291,28,'PM6','Original ACMG Summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable',0,''), -(1292,28,'PP1','Original ACMG Summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\nNot Applicable\nComments: Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available.',0,''), -(1293,28,'PP2','Original ACMG Summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable',0,''), -(1294,28,'PP3','Original ACMG Summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nInstructions:\nProtein: REVEL >.7333, RNA: multiple in silico predictors agree to a similar effect.',1,''), -(1295,28,'PP4','Original ACMG Summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\nNot Applicable',0,''), -(1296,28,'PP5','Original ACMG Summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.',0,''), -(1297,28,'BA1','Original ACMG Summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nInstructions:\nFiltering Allele Frequency >.5%.',1,''), -(1298,28,'BS1','Original ACMG Summary:\nAllele frequency is greater than expected for disorder.\n\nInstructions:\nFiltering Allele Frequency >.05%.',1,''), -(1299,28,'BS2','Original ACMG Summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\nNot Applicable',0,''), -(1300,28,'BS3','Original ACMG Summary:\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\n\nGene-specific modifications:\nModerate:\nUse when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.\n\nSupporting:\nUse when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.\n\nInstructions:\nFor protein, see detailed notes on ATM-specific assays, For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion).',1,''), -(1301,28,'BS4','Original ACMG Summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\nNot Applicable\nComments: AD Condition: Co-segregation analysis in lowpenetrance genes can lead to false positive results (PMID 32773770) . AR Condition: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.',0,''), -(1302,28,'BP1','Original ACMG Summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\nNot Applicable',0,''), -(1303,28,'BP2','Original ACMG Summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\n\nInstructions:\nUse ATM PM3/BP2 table.',1,''), -(1304,28,'BP3','Original ACMG Summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable',0,''), -(1305,28,'BP4','Original ACMG Summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\n Protein Analysis: Metapredictor REVEL score ≤.249\n RNA Analysis: Concordance of ≥2 predictors reflecting no predicted splice defect\n NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects)\n NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_O_Variable (a lack of observed RNA defect)\n NOTE: BP4 for protein predictors may be applied to BS3_Variable for protein effects. \n NOTE: BP4 could be used towards an RNA impact, a protein impact or both, as applicable. However, a variant\'s classification should be the sum of evidence for RNA or protein as tallied independently and should not mix-and-match evidence from RNA and protein evidence bodies. \n Example: Do not apply BP4 for in silico splice predictions toward the classification of a missense variant where all other evidence points towards a benign protein effect (instead apply PP3 or BP4, as applicable, for a protein predictor).\n\nInstructions:\nProtein: REVEL <.249, RNA: multiple in silico predictors agree to a lack of splice defect.',1,''), -(1306,28,'BP5','Original ACMG Summary:\nVariant found in a case with an alternate molecular basis for disease.\nNot Applicable',0,''), -(1307,28,'BP6','Original ACMG Summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.',0,''), -(1308,28,'BP7','Original ACMG Summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nGene-specific modifications:\nStrong/Moderate:\nCan be considered for BP7_O with curator discretion of quality.\n\nSupporting:\nCan be considered for BP7_O with curator discretion of quality, Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively\n\nInstructions:\nUse for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively. Use as BP7_O for synonymous and intronic variants with no splice defect observed. Weight for BP7_O is variable based on curator impression fo assay quality (not specified).',1,''), -(1309,29,'PVS1','Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease \n\nCaveats: \n- Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7) \n- Use caution interpreting LOF variants at the extreme 3\' end of a gene \n- Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact \n- Use caution in the presence of multiple transcripts',1,''), -(1310,29,'PS1','Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. \n\nExample: Val->Leu caused by either G>C or G>T in the same codon \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level',1,''), -(1311,29,'PS2','De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. \n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.',1,''), -(1312,29,'PS3','Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. \n\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.',1,''), -(1313,29,'PS4','The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. \n\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. \n\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.',1,''), -(1314,29,'PM1','Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.',1,''), -(1315,29,'PM2','Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. \n\nCaveat: Population data for indels may be poorly called by next generation sequencing.',1,''), -(1316,29,'PM3','For recessive disorders, detected in trans with a pathogenic variant. \n\nNote: This requires testing of parents (or offspring) to determine phase.',1,''), -(1317,29,'PM4','Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.',1,''), -(1318,29,'PM5','Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. \n\nExample: Arg156His is pathogenic, now you observe Arg156Cys. \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.',1,''), -(1319,29,'PM6','Assumed de novo, but without confirmation of paternity and maternity.',1,''), -(1320,29,'PP1','Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\nNote: May be used as stronger evidence with increasing segregation data.',1,''), -(1321,29,'PP2','Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.',1,''), -(1322,29,'PP3','Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.',1,''), -(1323,29,'PP4','Patient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.',1,''), -(1324,29,'BA1','Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC.',1,''), -(1325,29,'BS1','Allele frequency is greater than expected for disorder.',1,''), -(1326,29,'BS2','Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.',1,''), -(1327,29,'BS3','Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.',1,''), -(1328,29,'BS4','Lack of segregation in affected members of a family. \n\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.',1,''), -(1329,29,'BP1','Missense variant in a gene for which primarily truncating variants are known to cause disease',1,''), -(1330,29,'BP2','Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern.',1,''), -(1331,29,'BP3','In-frame deletions/insertions in a repetitive region without a known function',1,''), -(1332,29,'BP4','Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.',1,''), -(1333,29,'BP5','Variant found in a case with an alternate molecular basis for disease.',1,''), -(1334,29,'BP7','A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.',1,''), -(1335,30,'PVS1','Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease \n\nCaveats: \n- Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7) \n- Use caution interpreting LOF variants at the extreme 3\' end of a gene \n- Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact \n- Use caution in the presence of multiple transcripts',1,''), -(1336,30,'PS1','Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. \n\nExample: Val->Leu caused by either G>C or G>T in the same codon \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level',1,''), -(1337,30,'PS2','De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. \n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.',1,''), -(1338,30,'PS3','Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. \n\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.',1,''), -(1339,30,'PS4','The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. \n\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. \n\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.',1,''), -(1340,30,'PM1','Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.',1,''), -(1341,30,'PM2','Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. \n\nCaveat: Population data for indels may be poorly called by next generation sequencing.',1,''), -(1342,30,'PM3','For recessive disorders, detected in trans with a pathogenic variant. \n\nNote: This requires testing of parents (or offspring) to determine phase.',1,''), -(1343,30,'PM4','Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.',1,''), -(1344,30,'PM5','Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. \n\nExample: Arg156His is pathogenic, now you observe Arg156Cys. \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.',1,''), -(1345,30,'PM6','Assumed de novo, but without confirmation of paternity and maternity.',1,''), -(1346,30,'PP1','Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\nNote: May be used as stronger evidence with increasing segregation data.',1,''), -(1347,30,'PP2','Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.',1,''), -(1348,30,'PP3','Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.',1,''), -(1349,30,'PP4','Patient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.',1,''), -(1350,30,'BA1','Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC.',1,''), -(1351,30,'BS1','Allele frequency is greater than expected for disorder.',1,''), -(1352,30,'BS2','Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.',1,''), -(1353,30,'BS3','Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.',1,''), -(1354,30,'BS4','Lack of segregation in affected members of a family. \n\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.',1,''), -(1355,30,'BP1','Missense variant in a gene for which primarily truncating variants are known to cause disease',1,''), -(1356,30,'BP2','Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern.',1,''), -(1357,30,'BP3','In-frame deletions/insertions in a repetitive region without a known function',1,''), -(1358,30,'BP4','Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.',1,''), -(1359,30,'BP5','Variant found in a case with an alternate molecular basis for disease.',1,''), -(1360,30,'BP7','A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.',1,''), -(1496,31,'PVS1','Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease \n\nCaveats: \n- Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7) \n- Use caution interpreting LOF variants at the extreme 3\' end of a gene \n- Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact \n- Use caution in the presence of multiple transcripts',1,''); +INSERT INTO `classification_criterium` VALUES (1,2,'PVS1','Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease \n\nCaveats: \n- Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7) \n- Use caution interpreting LOF variants at the extreme 3\' end of a gene \n- Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact \n- Use caution in the presence of multiple transcripts',1,''),(2,2,'PS1','Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. \n\nExample: Val->Leu caused by either G>C or G>T in the same codon \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level',1,''),(3,2,'PS2','De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. \n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.',1,''),(4,2,'PS3','Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. \n\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.',1,''),(5,2,'PS4','The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. \n\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. \n\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.',1,''),(6,2,'PM1','Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.',1,''),(7,2,'PM2','Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. \n\nCaveat: Population data for indels may be poorly called by next generation sequencing.',1,''),(8,2,'PM3','For recessive disorders, detected in trans with a pathogenic variant. \n\nNote: This requires testing of parents (or offspring) to determine phase.',1,''),(9,2,'PM4','Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.',1,''),(10,2,'PM5','Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. \n\nExample: Arg156His is pathogenic; now you observe Arg156Cys. \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.',1,''),(11,2,'PM6','Assumed de novo, but without confirmation of paternity and maternity.',1,''),(12,2,'PP1','Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\nNote: May be used as stronger evidence with increasing segregation data.',1,''),(13,2,'PP2','Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.',1,''),(14,2,'PP3','Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.',1,''),(15,2,'PP4','Patient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.',1,''),(16,2,'PP5','Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation.',1,''),(17,2,'BA1','Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC.',1,''),(18,2,'BS1','Allele frequency is greater than expected for disorder.',1,''),(19,2,'BS2','Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.',1,''),(20,2,'BS3','Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.',1,''),(21,2,'BS4','Lack of segregation in affected members of a family. \n\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.',1,''),(22,2,'BP1','Missense variant in a gene for which primarily truncating variants are known to cause disease',1,''),(23,2,'BP2','Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.',1,''),(24,2,'BP3','In-frame deletions/insertions in a repetitive region without a known function',1,''),(25,2,'BP4','Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.',1,''),(26,2,'BP5','Variant found in a case with an alternate molecular basis for disease.',1,''),(27,2,'BP6','Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation.',1,''),(28,2,'BP7','A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.',1,''),(29,3,'PVS1','Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease \n\n Use SVI-approved decision tree to determine the strength of this criterion (refer to Abou Tayoun et al. for more details).',1,''),(30,3,'PS1','Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. \n\n Use original description with the following additions: \n PS1: \n - Must confirm there is no difference in splicing using RNA data. \n - Can only be used to compare to variants classified as Pathogenic or Likely Pathogenic by the TP53 VCEP (see ClinVar for VCEP classifications). \n\n PS1_Moderate: \n - Must confirm there is no difference in splicing using a metapredictor. \n - Can only be used to compare to variants classified as Pathogenic or Likely Pathogenic by the TP53 VCEP (see ClinVar).',1,''),(31,3,'PS2','De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. \n\n Use SVI-approved scoring system to determine the strength of this criterion (refer to Table 2 from original publication: PMC8374922 (linked above) for more details)',1,''),(32,3,'PS3','Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. \n\n The following additions have been made by the TP53 ACMG specification: \n - PS3: transactivation assays in yeast demonstrate a low functioning allele (≤20% activity) AND there is evidence of dominant negative effect and loss-of-function OR there is a second assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays).\n\n - PS3_Moderate: transactivation assays in yeast demonstrate a partially functioning allele (>20% and ≤75% activity) AND there is evidence of dominant negative effect and loss-of-function OR there is a second assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays).\n\n - PS3_Moderate: there is no data available from transactivation assays in yeast BUT there is evidence of dominant negative effect and loss-of-function AND there is a second assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays).\n\n ==> Refer to Figure 1 from original publication: PMC8374922 (linked above) for more details.',1,''),(33,3,'PS4','The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. \n\n Use SVI-approved scoring system to determine the strength of this criterion (refer to Table 3 from original publication: PMC8374922 (linked above) for more details). This criterion cannot be applied when a variant also meets BA1 or BS1. Refrain from considering probands who have another pathogenic variant(s) in a highly penetrant cancer gene(s) that is a logical cause for presentation. \n\n Caveat: \n Please be mindful of the risk of clonal hematopoieses of indeterminate potential with TP53 variants (Coffee et al., 2017; Weitzel et al., 2017). One should take care to ensure that probands have germline and not mosaic somatic TP53 variants.',1,''),(34,3,'PM1','Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. \n\n Located in a mutational hotspot defined as: \n - Variants within the following codons on protein NP_000537.3: 175, 273, 245, 248, 282, 249. \n - Variants seen in cancerhotspots.org (v2) with >10 somatic occurrences (recommendation from the ClinGen Germline/Somatic Variant Curation Subcommittee).',1,''),(35,3,'PM2','Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. \n\n Caveat: Population data for indels may be poorly called by next generation sequencing. \n\n PM2_Supporting: absent from population databases (gnomAD (most up-to-date non-cancer dataset) is the preferred population database at this time http:#gnomad.broadinstitute.org).',1,''),(36,3,'PM3','Excluded.',0,''),(37,3,'PM4','Excluded.',0,''),(38,3,'PM5','Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. \n\n Example: Arg156His is pathogenic; now you observe Arg156Cys. \n\n PM5: novel missense change at an amino acid residue where at least two other different missense changes determined to be pathogenic by the TP53 VCEP have been seen before. PM5_Supporting: novel missense change at an amino acid residue where a different missense change determined to be pathogenic by the TP53 VCEP has been seen before. \n\n Both criteria require the following additions: \n - Grantham should be used to compare the variants, and the variant being evaluated must have equal to or higher score than the observed pathogenic variants. \n - Splicing should be ruled out using a metapredictor. \n - This criterion cannot be applied when a variant also meets PM1.',1,''),(39,3,'PM6','Assumed de novo, but without confirmation of paternity and maternity. \n\n Use SVI-approved scoring system to determine the strength of this criterion (refer to Table 2 from original publication: PMC8374922 (linked above) for more details).',1,''),(40,3,'PP1','Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\n PP1: co-segregation with disease is observed in 3–4 meioses in one family. \n PP1_Moderate: co-segregation with disease is observed in 5–6 meioses in one family. \n PP1_Strong: co-segregation with disease is observed >7 meioses in >1 family.',1,''),(41,3,'PP2','Excluded.',0,''),(42,3,'PP3','Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). \n\n Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. \n\n PP3: Use original description with the following additions: \n - For missense variants, use a combination of BayesDel (≥0.16) and optimised Align-GVGD (C55-C25). \n - For splicing variants, use a metapredictor. \n\n PP3_Moderate: for missense variants, use a combination of BayesDel (≥0.16) and optimized Align-GVGD (C65).',1,''),(43,3,'PP4','Excluded.',0,''),(44,3,'PP5','Excluded.',0,''),(45,3,'BA1','Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC.\n\n Allele frequency is ≥0.1% in a non-founder population with a minimum of five alleles (gnomAD (most up-to-date non-cancer dataset)) is the preferred population database at this time http:#gnomad.broadinstitute.org).',1,''),(46,3,'BS1','Allele frequency is greater than expected for disorder. \n\n Allele frequency is ≥0.03% and <0.1% in a non-founder population with a minimum of five alleles (gnomAD (most up-to-date non-cancer dataset) is the preferred population database at this time http:#gnomad.broadinstitute.org).',1,''),(47,3,'BS2','Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.\n\n BS2: observed in a single dataset in ≥8 females, who have reached at least 60 years of age without cancer (i.e. cancer diagnoses after age 60 are ignored). \n\n BS2_Supporting: observed in a single dataset in 2–7 females, who have reached at least 60 years of age without cancer. \n\n Caveat: Be mindful of the risk of clonal hematopoiesis of indeterminate potential with TP53 variants (Coffee et al., 2017; Weitzel et al., 2017). Individuals with mosaic somatic TP53 variants should not be included as evidence for BS2.',1,''),(48,3,'BS3','Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. \n\n - BS3: transactivation assays in yeast demonstrate a functional allele or super-transactivation (>75% activity) AND there is no evidence of dominant negative effect and loss-of-function OR there is a second assay showing retained function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays). \n\n - BS3_Supporting: transactivation assays in yeast demonstrate a partially functioning allele (>20% and ≤75% activity) AND there is no evidence of dominant negative effect and loss-of-function OR there is a second assay showing retained function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays). \n\n - BS3_Supporting: there is no data available from transactivation assays in yeast BUT there is no evidence of dominant negative effect and loss-of-function AND there is a second assay showing retained function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays). \n\n ==> Refer to Figure 1 from original publication: PMC8374922 (linked above) for more details.',1,''),(49,3,'BS4','Lack of segregation in affected members of a family. \n\n The variant segregates to opposite side of the family meeting LFS criteria, or the variant is present in >3 living unaffected individuals (at least two of three should be female) above 55 years of age.',1,''),(50,3,'BP1','Excluded',0,''),(51,3,'BP2','Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern. \n\n Variant is observed in trans with a TP53 pathogenic variant (phase confirmed), or there are three or more observations with a TP53 pathogenic variant when phase is unknown (at least two different TP53 pathogenic variants). The other observed pathogenic variants must have been classified using the TP53-specific guidelines.',1,''),(52,3,'BP3','Excluded',0,''),(53,3,'BP4','Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) \n\n Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. \n\n Same rule description with the following additions: \n - For missense variants, use a combination of BayesDel (<0.16) and optimized Align-GVGD (C15-C0). \n - For splicing variants, use a metapredictor.',1,''),(54,3,'BP5','Excluded',0,''),(55,3,'BP6','Excluded',0,''),(56,3,'BP7','A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. \n\n Same description with the following additions: \n - Splicing should be ruled out using a metapredictor. \n - If a new alternate site is predicted, compare strength to native site in interpretation.',1,''),(57,4,'PVS1','Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease \n\n - Very strong: Per ClinGen SVI guidelines with the exception of canonical splice sites \n - Strong: Per ClinGen SVI guidelines. Use the strong strength of evidence for canonical splice sites. \n caveat: \n CDH1 exonic deletions or tandem duplications of in-frame exon truncations in NMD-resistant zone located upstream the most 3\' well characterized pathogenic variant c.2506G>T (p.Glu836Ter). Use moderate strength if premature stop is downstream of this variant \n - Moderate: Per ClinGen SVI guidelines. \n caveats: \n 1. G to non-G variants disrupting the last nucleotide of an exon \n 2. Canonical splice sites located in exons demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site) - Supporting: Per ClinGen SVI guidelines. \n\n Additional comment: \n RNA analysis is recommended for splicing alterations, and if the RNA evidence does not support the prediction, the strength should be updated PP3 cannot be applied for canonical splice sites',1,''),(58,4,'PS1','Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. \n\n Example: Val->Leu caused by either G>C or G>T in the same codon \n Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level \n\n Additional comment: \n Variant must not impact splicing.',1,''),(59,4,'PS2','De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. \n \n Strength specifications: \n - Very strong: ≥2 patients with DGC and/or LBC w/parental confirmation - Strong: 1 patient with DGC and/or LBC w/parental confirmation \n Additional comment: \n Use ClinGen\'s de novo point system for a highly specific phenotype (see Table S2 from original publication linked at the top of the page)',1,''),(60,4,'PS3','Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. \n\n Strength specifications: \n - Strong: RNA assay demonstrating abnormal out-of-frame transcripts \n - Supporting: RNA assay demonstrating abnormal in-frame transcripts \n Additional comment: \n This rule can only be applied to demonstrate splicing defects.',1,''),(61,4,'PS4','The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. \n\n Strength specifications: \n - Very strong: 16 families meet HDGC criteria \n - Strong: 4 families meet HDGC criteria \n - Moderate: 2 families meet HDGC criteria \n - Supporting: 1 family meets HDGC criteria \n\n Additional comment: \n This rule assumes 30% penetrance in individuals with pathogenic variants. For example, if the variant in observed in 3 families, at least one of those families need to meet criteria for HDGC in order to apply this rule. PS4 cannot be applied to variants that meet BS1 or BA1',1,''),(62,4,'PM1','Excluded.',0,''),(63,4,'PM2','Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. \n\n <1/100,000 alleles in gnomAD cohort; if present in ≥2 individuals, must be present in <1/50,000 alleles within a sub-population \n\n Additional comment: \n Use gnomAD to determine allele frequency. Beware of technical limitations that can inaccurately represent allele frequency in this population database',1,''),(64,4,'PM3','Excluded',0,''),(65,4,'PM4','Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. \n\n Additional comment: \n No rule specification proposed. Variant example - CDH1 c.2647T>C (p.Ter883Glnext*29)',1,''),(66,4,'PM5','Excluded',0,''),(67,4,'PM6','Assumed de novo, but without confirmation of paternity and maternity. \n\n Strength specification: \n - Very strong: ≥4 patients with DGC and/or LBC w/o parental confirmation \n - Strong: ≥2 patients with DGC and/or LBC w/o parental confirmation \n - Moderate: 1 patient with DGC and/or LBC w/o parental confirmation \n\n Additional comment: \n Use ClinGen\'s de novo point system for a highly specific phenotype (See Table S2 of original publication linked at the top of this page)',1,''),(68,4,'PP1','Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\n Strength specification: \n - Strong: ≥7 meioses across ≥2 families \n - Moderate: 5-6 meioses across ≥1 families \n - Supporting: 3-4 meioses across ≥1 families \n\n Additional comment: \n Based strength of rule code on number of meioses across one or more families.',1,''),(69,4,'PP2','Excluded',0,''),(70,4,'PP3','Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). \n\n Strength specification: \n - Moderate: Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/RNA predictions \n - Supporting: At least 3 in silico splicing predictors in agreement (.Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder) \n\n Additional comment: \n Rule code is only for non-canonical splicing variants. Code also does not apply to last nucleotide of exon 3 (c.387G). Do not use protein-based computational prediction models for missense variants',1,''),(71,4,'PP4','Use PS4 in place of PP4.',1,''),(72,4,'PP5','Excluded',0,''),(73,4,'BA1','Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC. \n\n MAF cutoff of 0.2% \n\n Additional comment: \n 99.99% CI; subpopulation must have a minimum of 5 alleles present.',1,''),(74,4,'BS1','Allele frequency is greater than expected for disorder. \n\n Stand alone: MAF cutoff of 0.1% \n\n Additional comment: \n 99.99% CI; subpopulation must have a minimum of 5 alleles present',1,''),(75,4,'BS2','Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age. \n\n Strength specification: \n - Strong: Variant seen in ≥10 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC \n - Supporting: Variant seen in ≥3 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC ',1,''),(76,4,'BS3','Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. \n Functional RNA studies demonstrating no impact on transcript composition. \n\n Additional comment: \n This rule can only be used to demonstrate lack of splicing and can be downgraded based on quality of data.',1,''),(77,4,'BS4','Lack of segregation in affected members of a family. \n\n Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. \n\n Additional comment: \n Beware of the presence of phenocopies (e.g., breast cancer) that can mimic lack of segregation. Also, families may have more than one pathogenic variant contributing to another AD disorder',1,''),(78,4,'BP1','Excluded',0,''),(79,4,'BP2','Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern. \n\n Strength specifications: \n - Strong: Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors \n - Supporting: Variant is observed in cis (or phase is unknown) w/ a pathogenic variant \n\n Additional comment: \n Evidence code is dependent on strength of data. Take consideration of quality of sequencing data when applying code. Note that code requires knowledge of individuals\' phenotype. Therefore, data from population databases should only be used when phenotypic info is available.',1,''),(80,4,'BP3','Excluded',0,''),(81,4,'BP4','Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) \n\n Splicing predictions only. At least 3 in silico splicing predictors in agreement (Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder) \n\n Additional comment: \n This rule can only be used when splicing predictions models suggest no impact on protein. Do not use protein based computational prediction models for missense. variants',1,''),(82,4,'BP5','Variant found in a case with an alternate molecular basis for disease. \n\n Additional comment: \n This applies if a P/LP variant is identified in an alternate gene known to cause HDGC (e.g., CTNNA1)',1,''),(83,4,'BP6','Excluded',0,''),(84,4,'BP7','A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. \n\n Synonymous variants where nucleotide is not highly conserved; variant is the reference nucleotide in 1 primate and/or >3 mammal species \n\n Additional comment: \n Note the CDH1 rule specification does not require a benign in silico splice prediction. This allows use with BP4, as appropriate, to classify variants meeting both criteria as likely benign ',1,''),(85,5,'1.1','Allele frequency ≥ 1 % (MAF ≥ 0.01) in large populations like Caucasians, Africans or Asians. \n\n CAVE: Allele freuqency ≥ 1 % in subpopulations with low mixed gene pool (e. g. Finnish populations, Foundermutations) does NOT suffice this criterium.',1,''),(86,5,'1.2','Variants with a multifactorial calculated pobability of < 0,001 (< 0,1 %) to be pathogenic. \n\n CAVE: Currently only applicable to BRCA1/2.',1,''),(87,5,'1.3','Variants in high risk genes which occur in at least 10 individuals within suitable groups of non-diseased individuals (e. g. FLOSSIES).',1,''),(88,5,'2.1','Allele frequency between 0.5 and 1 % (MAF 0.005–0,01) in large populations like Caucasians, Africans or Asians. \n\n CAVE: Allele freuqency between 0.5 and 1 % in subpopulations with low mixed gene pool (e. g. Finnish populations, Foundermutations) does NOT suffice this criterium.',1,''),(89,5,'2.2','Either exonic variants (A), which lead to the substitution of an amino acid (missense variants), or small in-frame insertions/ deletions, which lead to insertions/deletions of one or amino acid(s) and whose a priori probability for pathogenicity is for pathogenicity is ≤ 2% (A-GVGD analysis, http:#priors.hci.utah.edu/PRIORS/), and (B) synonymous variants, if these variants (A, B) are likely to be pathogenic according to bioinformatic prediction programs the splicing result with a high probability and (A) are outside the relevant and (A) are located outside of the relevant functional domains defined by the VUS task-force (see tables A5.1–5.9 from the original proposal linked at the top of this page). For the non-BRCA1/2 genes, the above variants must be In large populations with an allele frequency of. 0.001 ≤ MAF < 0.01 (0.1-1%).',1,''),(90,5,'2.3','Synonymous substitutions or intronic variants, which do not contain mRNA aberrations in the form of exon deletions/ duplications or monoallelic expression of the wild-type transcript in RNA analyses. This applies even if they are likely to alter the splice-result according to bioinformatic prediction programs (for programs and thresholds, see Appendix A1 of the original proposal liked at the top of this page).',1,''),(91,5,'2.4','Variants that occur in the same gene with a clearly pathogenic variant in trans (co-occurrence). It must be confirmed that a homozygous or compound heterozygous genotype is associated with a known clinically distinct phenotype.',1,''),(92,5,'2.5','Variants with a multifactorial calculated probability to be pathogenic of 0.001-0.049. \n\n CAVE: Does only apply to BRCA1/2.',1,''),(93,5,'2.6','Exonic variants which cause an amino acid change equal to a known class 1 variant, but encode a different nucleotide change. Additionally, the variant must not show a conspicious splice prediction.',1,''),(94,5,'2.7','Missense variants which have information from functional analyses (or similar). These, however, do not suffice for a multifactorial classification. Additionally, the variant was previously classified by expert panels like ENIGMA or the ClinGen-expert-group as class 2',1,''),(95,5,'2.8','Suitable functional analyses do not show a loss of function or functional relevance. Additionally there must not be contradictory data. \n\n Comment: The suitable functional analyses are dependent on the gene of the variant.',1,''),(96,5,'2.9','Paired LOH-analyses in blood or tumor samples show a loss of the allele which contains the variant under consideration. This was proven among tumor tissue (BC or OC).',1,''),(97,5,'2.10','Variants within genes of intermediate risk without hints to potential function loss. These variants must also occour in at least 20 individuals of suitable non-diseased cohorts (e. g. FLOSSIES) \n\n CAVE: Exceptions are possible in case of frequent foundermutations (e. g. CHEK2, c.1100del).',1,''),(98,5,'3.1','A special case in which the criteria clearly state a certain classification. However, the variant is listed among the special cases of the genes or other exceptions occur (see table 5 of the original proposal linked at the top of the page)',1,''),(99,5,'3.2','Variants with controversial data with regards to its classification.',1,''),(100,5,'3.3','Variants which can be found within -20 to +3 bp and -3 to +8 bp from an exon/intron border. This applies only if there is no in-vitro mRNA analysis and criteria 4.3, 4.4 or 2.6 do not apply.',1,''),(101,5,'3.4','Exon duplications without additional analyses (e. g. cDNA analyses, break-point analyses, ...)',1,''),(102,5,'3.5','Variants with a multifaktorial calculated pathogenicity probability between 0.05 and 0.949. \n\n CAVE: This criterium only applies to BRCA1/2 variants.',1,''),(103,5,'4.1','Variants with a multifaktorial calculated pathogenicity probability between 0.95 and 0.99. \n\n CAVE: This criterium only applies to BRCA1/2 variants.',1,''),(104,5,'4.2','Variants which encode an early stop of the protein synthesis (nonsense- or frameshift variants). In addition, variants must not cause damage to known clinical relevant functional protein domains as long as the induced stop codon is found approximately 50 bp upstream from the last exon-exon-junction. \n\n Comment: If there is at least one exon-exon-junction complex downstream of the new, early stop codon, the early one would be able to recruit the Upf1 and, thus, induce nonsense-mediated decay (NMD))',1,''),(105,5,'4.3','Intronic variants at position ± 1,2 or a G to A/T or C change at the last position of the exon. Apply this criterium if there is a positive splice prediction and there is no mRNA analysis. \n\n CAVE: Applies to BRCA1/2 variants at the last position of the exon only if the first 6 bases within the intron are not equal to \"GTRRGT\". \n\n Exceptions: \n - A cryptic spice site (AG/GT) is activated by the variant and the (predicted) new exon yields in-frame splicing --> class 3 \n - A transcript with (predicted) skipped exon(s) exists as a relevant alternatively spliced transcipt --> class 3 \n - The (predicted) skipped exon(s) is spliced in-frame and does not contain known functional domains --> class 3',1,''),(106,5,'4.4','Variants which cause the same amino acid change as a known class 5 pathogenic missence variant, but is characterized by another nucleotide change. Also, it is required that there is no prediction of abberant splicing.',1,''),(107,5,'4.5','In-frame deletions which cause the loss of a class 5 missence variant and which disrupt or cause the loss of funcionally important protein domains.',1,''),(108,5,'4.6','In-frame insertions which were verified via in-vitro mRNA analyses, that disrupt functionally important protein domains.',1,''),(109,5,'4.7','Variants which cause a change in the tranlation initiation codon (AUG, Methionin). Additionally, there must not be evidence (e. g. close alternative start-codon) for an alternative classification.',1,''),(110,5,'4.8','Variants which do have information from functional analyses, clinical data, or other evidence that do, however, not suffice for a multifactorial classification and which were classified as class 4 by expert panels like ENIGMA or ClinGen.',1,''),(111,5,'4.9','Variants which have functional analyses that depict loss of function or another functional relevance and which do not have contradictory information.',1,''),(112,5,'5.1','Nonsense- or frameshift variants which induce an early stop codon. This stop codon prevents the expression of known relevant functional protein domains.',1,''),(113,5,'5.2','Variants with a multifactorial calculated probability to be pathogenic of more than 0.99. \n\n CAVE: Only applies to BRCA1/2.',1,''),(114,5,'5.3','Splice variants which were shown to induce a frame shift that causes an early stop of the proteinbiosynthesis and, thus, prevents the expression of known relevant functional protein domains. This was proven via in-vitro mRNA analyses. It is also important that NO wildtype transcript of the mutated allele is detectable (monoallelic expression).',1,''),(115,5,'5.4','Splice variants in which an invitro mRNA analysis has detected an in-frame deletion/insertion that leads to the interruption or loss of a known clinically relevant domain or to a change in the protein structure which functionally inactivates the protein. It is also important that NO wildtype transcript of the mutated allele is detectable (monoallelic expression).',1,''),(116,5,'5.5','Copy number deletions which cause the disruption or loss of (an) exon(s) which contain clinically relevant functional domain(s) or which cause a predicted inactivation of known clinically relevant functional domains due to a frame shift.',1,''),(117,5,'5.6','Copy number duplications of any size which were proven (with lab-analyses) to duplicate one or multiple exons that cause a frame shift and, thus, inactivate known clinically relevant functional protein domains.',1,''),(118,6,'1.1','Allele frequency ≥ 1 % (MAF ≥ 0.01) in large populations like Caucasians, Africans or Asians. \n\n CAVE: Allele freuqency ≥ 1 % in subpopulations with low mixed gene pool (e. g. Finnish populations, Foundermutations) does NOT suffice this criterium.',1,''),(119,6,'1.2','Variants with a multifactorial calculated pobability of < 0,001 (< 0,1 %) to be pathogenic. \n\n CAVE: Currently only applicable to BRCA1/2.',1,''),(120,6,'1.3','Variants in high risk genes which occur in at least 10 individuals within suitable groups of non-diseased individuals (e. g. FLOSSIES).',1,''),(121,6,'2.1','Allele frequency between 0.5 and 1 % (MAF 0.005–0,01) in large populations like Caucasians, Africans or Asians. \n\n CAVE: Allele freuqency between 0.5 and 1 % in subpopulations with low mixed gene pool (e. g. Finnish populations, Foundermutations) does NOT suffice this criterium.',1,''),(122,6,'2.2','Either exonic variants (A), which lead to the substitution of an amino acid (missense variants), or small in-frame insertions/ deletions, which lead to insertions/deletions of one or amino acid(s) and whose a priori probability for pathogenicity is for pathogenicity is ≤ 2% (A-GVGD analysis, http:#priors.hci.utah.edu/PRIORS/), and (B) synonymous variants, if these variants (A, B) are likely to be pathogenic according to bioinformatic prediction programs the splicing result with a high probability and (A) are outside the relevant and (A) are located outside of the relevant functional domains defined by the VUS task-force (see tables A5.1–5.9 from the original proposal linked at the top of this page). For the non-BRCA1/2 genes, the above variants must be In large populations with an allele frequency of. 0.001 ≤ MAF < 0.01 (0.1-1%).',1,''),(123,6,'2.3','Synonymous substitutions or intronic variants, which do not contain mRNA aberrations in the form of exon deletions/ duplications or monoallelic expression of the wild-type transcript in RNA analyses. This applies even if they are likely to alter the splice-result according to bioinformatic prediction programs (for programs and thresholds, see Appendix A1 of the original proposal liked at the top of this page).',1,''),(124,6,'2.4','Variants that occur in the same gene with a clearly pathogenic variant in trans (co-occurrence). It must be confirmed that a homozygous or compound heterozygous genotype is associated with a known clinically distinct phenotype.',1,''),(125,6,'2.5','Variants with a multifactorial calculated probability to be pathogenic of 0.001-0.049. \n\n CAVE: Does only apply to BRCA1/2.',1,''),(126,6,'2.6','Exonic variants which cause an amino acid change equal to a known class 1 variant, but encode a different nucleotide change. Additionally, the variant must not show a conspicious splice prediction.',1,''),(127,6,'2.7','Missense variants which have information from functional analyses (or similar). These, however, do not suffice for a multifactorial classification. Additionally, the variant was previously classified by expert panels like ENIGMA or the ClinGen-expert-group as class 2',1,''),(128,6,'2.8','Suitable functional analyses do not show a loss of function or functional relevance. Additionally there must not be contradictory data. \n\n Comment: The suitable functional analyses are dependent on the gene of the variant.',1,''),(129,6,'2.9','Paired LOH-analyses in blood or tumor samples show a loss of the allele which contains the variant under consideration. This was proven among tumor tissue (BC or OC).',1,''),(130,6,'2.10','Variants within genes of intermediate risk without hints to potential function loss. These variants must also occour in at least 20 individuals of suitable non-diseased cohorts (e. g. FLOSSIES) \n\n CAVE: Exceptions are possible in case of frequent foundermutations (e. g. CHEK2, c.1100del).',1,''),(131,6,'3.1','A special case in which the criteria clearly state a certain classification. However, the variant is listed among the special cases of the genes or other exceptions occur (see table 5 of the original proposal linked at the top of the page)',1,''),(132,6,'3.2','Variants with controversial data with regards to its classification.',1,''),(133,6,'3.3','Variants which can be found within -20 to +3 bp and -3 to +8 bp from an exon/intron border. This applies only if there is no in-vitro mRNA analysis and criteria 4.3, 4.4 or 2.6 do not apply.',1,''),(134,6,'3.4','Exon duplications without additional analyses (e. g. cDNA analyses, break-point analyses, ...)',1,''),(135,6,'3.5','Variants with a multifaktorial calculated pathogenicity probability between 0.05 and 0.949. \n\n CAVE: This criterium only applies to BRCA1/2 variants.',1,''),(136,6,'4.1','Variants with a multifaktorial calculated pathogenicity probability between 0.95 and 0.99. \n\n CAVE: This criterium only applies to BRCA1/2 variants.',1,''),(137,6,'4.2','Variants which encode an early stop of the protein synthesis (nonsense- or frameshift variants). In addition, variants must not cause damage to known clinical relevant functional protein domains as long as the induced stop codon is found approximately 50 bp upstream from the last exon-exon-junction. \n\n Comment: If there is at least one exon-exon-junction complex downstream of the new, early stop codon, the early one would be able to recruit the Upf1 and, thus, induce nonsense-mediated decay (NMD))',1,''),(138,6,'4.3','Intronic variants at position ± 1,2 or a G to A/T or C change at the last position of the exon. Apply this criterium if there is a positive splice prediction and there is no mRNA analysis. \n\n CAVE: Applies to BRCA1/2 variants at the last position of the exon only if the first 6 bases within the intron are not equal to \"GTRRGT\". \n\n Exceptions: \n - A cryptic spice site (AG/GT) is activated by the variant and the (predicted) new exon yields in-frame splicing --> class 3 \n - A transcript with (predicted) skipped exon(s) exists as a relevant alternatively spliced transcipt --> class 3 \n - The (predicted) skipped exon(s) is spliced in-frame and does not contain known functional domains --> class 3',1,''),(139,6,'4.4','Variants which cause the same amino acid change as a known class 5 pathogenic missence variant, but is characterized by another nucleotide change. Also, it is required that there is no prediction of abberant splicing.',1,''),(140,6,'4.5','In-frame deletions which cause the loss of a class 5 missence variant and which disrupt or cause the loss of funcionally important protein domains.',1,''),(141,6,'4.6','In-frame insertions which were verified via in-vitro mRNA analyses, that disrupt functionally important protein domains.',1,''),(142,6,'4.7','Variants which cause a change in the tranlation initiation codon (AUG, Methionin). Additionally, there must not be evidence (e. g. close alternative start-codon) for an alternative classification.',1,''),(143,6,'4.8','Variants which do have information from functional analyses, clinical data, or other evidence that do, however, not suffice for a multifactorial classification and which were classified as class 4 by expert panels like ENIGMA or ClinGen.',1,''),(144,6,'4.9','Variants which have functional analyses that depict loss of function or another functional relevance and which do not have contradictory information.',1,''),(145,6,'5.1','Nonsense- or frameshift variants which induce an early stop codon. This stop codon prevents the expression of known relevant functional protein domains.',1,''),(146,6,'5.2','Variants with a multifactorial calculated probability to be pathogenic of more than 0.99. \n\n CAVE: Only applies to BRCA1/2.',1,''),(147,6,'5.3','Splice variants which were shown to induce a frame shift that causes an early stop of the proteinbiosynthesis and, thus, prevents the expression of known relevant functional protein domains. This was proven via in-vitro mRNA analyses. It is also important that NO wildtype transcript of the mutated allele is detectable (monoallelic expression).',1,''),(148,6,'5.4','Splice variants in which an invitro mRNA analysis has detected an in-frame deletion/insertion that leads to the interruption or loss of a known clinically relevant domain or to a change in the protein structure which functionally inactivates the protein. It is also important that NO wildtype transcript of the mutated allele is detectable (monoallelic expression).',1,''),(149,6,'5.5','Copy number deletions which cause the disruption or loss of (an) exon(s) which contain clinically relevant functional domain(s) or which cause a predicted inactivation of known clinically relevant functional domains due to a frame shift.',1,''),(150,6,'5.6','Copy number duplications of any size which were proven (with lab-analyses) to duplicate one or multiple exons that cause a frame shift and, thus, inactivate known clinically relevant functional protein domains.',1,''),(749,21,'PVS1','ACMG summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nNull variant (nonsense, frameshift, splice site (donor/acceptor +/-1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\nIn alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5_PTC code (See Appendix D for details).\nInstructions:\nSee Specifications Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the BRCA1 and BRCA2 PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor +/- 1,2)) - organized by exon. See Appendix Figure 3,4 and Table 5 for further justification.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.',1,''),(750,21,'PS1','ACMG summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nStrong:\nApply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1, for exonic and intronic variants with same predicted impact on splicing, as a previously classified pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \nSee Specifications Table 5 and Appendix E, J and K for details.\n\nModerate:\nApply PS1_Moderate, for predicted missense substitutions, where previously classified likely pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1_Moderate, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\nSupporting:\nApply PS1_Supporting, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\nInstructions:\nFor both missense and splicing scenarios, (Likely) Pathogenic variant classification should be assigned using VCEP specifications.\nFor application of PS1 for splicing predictions, see Specifications Table 5. The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the variant and the previously classified pathogenic variant should also be considered before PS1 code application for splicing prediction.',1,''),(751,21,'PS2','ACMG summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''),(752,21,'PS3','ACMG summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''),(753,21,'PS4','ACMG summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.\nModification Type: Clarification,Gene-specific\n\nInstructions:\nCase dataset should be ethnicity and country-matched to control dataset. If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). Do not use Proband Counting as originally described.',1,''),(754,21,'PM1','ACMG summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''),(755,21,'PM2','ACMG summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-Specific modifications:\nAbsent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.\nModification Type: Gene-specific\n\nInstructions:\nObservation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth <25 at region around the variant.',1,''),(756,21,'PM3','ACMG summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nApply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3_Strong = ≥4 points\nPM3 = 2 points\nPM3_Supporting = 1 point\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nVariant under assessment must be sufficiently rare (meet PM2_Supporting, or PM2 not applicable).\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\nFor related individuals score only most severe presentation.\nAlso see Specifications Table 6 for additional stipulations',1,''),(757,21,'PM4','ACMG summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''),(758,21,'PM5','ACMG summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nProtein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.\n\nInstructions:\nOnly applied to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). See Specifications Table 4, provided as a separate searchable excel file, for PM5_PTC codes applicable for predicted termination codon variants - organized by exon.',1,''),(759,21,'PM6','ACMG summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''),(760,21,'PP1','ACMG summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\nPP1_Very Strong - LR>350:1\nPP1_Strong - LR>18.7:1\nPP1_Moderate - LR>4.3:1\nPP1 - LR >2.08:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.\nStipulation: to apply code as Pathogenic Very Strong, VUS should have bioinformatically predicted (or experimentally proven) effect on protein or mRNA splicing. If co-segregation score is from a single family, or several families from an isolated population, assess the possibility of a different causative pathogenic variant.',1,''),(761,21,'PP2','ACMG summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: High frequency of benign missense variants.',0,''),(762,21,'PP3','ACMG summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nApply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857.\nApply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.\nSee Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''),(763,21,'PP4','ACMG summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\n\nGene-specific modifications:\nBreast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4_Very Strong - LR>350:1\nPP4_Strong - LR>18.7:1\nPP4_Moderate - LR>4.3:1\nPP4 - LR >2.08:1 \nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\nSee Specifications Table7 and Appendix B for details.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''),(764,21,'PP5','ACMG summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''),(765,21,'BA1','ACMG summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nFilter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''),(766,21,'BS1','ACMG summary:\nAllele frequency is greater than expected for disorder.\n\nStrong:\nFilter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nSupporting:\nFilter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''),(767,21,'BS2','ACMG summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nApplied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See Specifications Table 8 for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2 = ≥ 4 points\nBS2_Moderate = 2 points\nBS2_Supporting = 1 points\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nSee Specifications Table 8 for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\nAlso see Specifications Table 8 for additional stipulations.',1,''),(768,21,'BS3','ACMG summary:\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of no damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''),(769,21,'BS4','ACMG summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nLack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\nBS4_VeryStrong - LR <0.00285:1\nBS4 - LR <0.05:1\nBS4_Moderate - LR <0.23:1\nBS4_Supporting - LR 0.23-0.48:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.',1,''),(770,21,'BP1','ACMG summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\n\nGene-specific modifications:\nApply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact. Missense prediction not applicable.',1,''),(771,21,'BP2','ACMG summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\nNot Applicable\nComments: Applied only in the context of BS2.',0,''),(772,21,'BP3','ACMG summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details',0,''),(773,21,'BP4','ACMG summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nMissense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.15 AND SpliceAI ≤0.1).\nSilent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).\nIntronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''),(774,21,'BP5','ACMG summary:\nVariant found in a case with an alternate molecular basis for disease.\n\nGene-specific modifications:\nUse ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5_VeryStrong - LR <0.00285:1\nBP5_Strong - LR <0.05:1\nBP5_Moderate - LR <0.23:1\nBP5 - LR 0.23-0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast-ovarian cancer risk genes have no specific phenotype.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''),(775,21,'BP6','ACMG summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''),(776,21,'BP7','ACMG summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nStrong:\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile - mRNA assay only. Apply as BP7 (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nSupporting:\nSilent variant inside a (potentially) clinically important functional domain, IF BP4 met.\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\nSee Specifications Figure1A and Appendix J for additional details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained. Not applicable for missense variants inside a (potentially) clinically important functional domain as they may still impact protein function through the amino acid change.\nFollowing convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI ≤0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. See Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''),(777,22,'PVS1','ACMG summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nNull variant (nonsense, frameshift, splice site (donor/acceptor +/-1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nIn alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5_PTC code (See Appendix D for details).\nSee Specifications Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the BRCA1 and BRCA2 PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor ±1,2)) – organized by exon. See Appendix Figure 5,6 and Table 5 for further justification.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.',1,''),(778,22,'PS1','ACMG summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nStrong:\nApply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1, for exonic and intronic variants with same predicted impact on splicing, as a previously classified pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \nSee Specifications Table 5 and Appendix E, J and K for details.\n\nModerate:\nApply PS1_Moderate, for predicted missense substitutions, where a previously classified likely pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\nApply PS1_Moderate, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\nSupporting:\nApply PS1, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\nSee Specifications Table 5 and Appendix E, J and K for details.\n\n\nInstructions:\nFor both missense and splicing scenarios, (Likely) Pathogenic variant classification should be assigned using VCEP specifications.\nFor application of PS1 for splicing predictions, see Specifications Table 5. The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the variant and the established pathogenic variant should also be considered before PS1 code application for splicing prediction.',1,''),(779,22,'PS2','ACMG summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot Applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''),(780,22,'PS3','ACMG summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of a damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''),(781,22,'PS4','ACMG summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.\n\nInstructions:\nCase dataset should be ethnicity and country-matched to control dataset. If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). Do not use Proband Counting as originally described.',1,''),(782,22,'PM1','ACMG summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''),(783,22,'PM2','ACMG summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nAbsent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.\n\nInstructions:\nObservation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth <25 at region around the variant.',1,''),(784,22,'PM3','ACMG summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nStrong:\nApply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\nPM3_Strong = ≥4 points\n\nModerate:\nApply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\nPM3 = 2 points\n\nSupporting:\nApply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\nPM3_Supporting = 1 point\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nVariant under assessment must be sufficiently rare (meet PM2_Supporting, or PM2 not applicable).\nSee Specifications Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\nFor related individuals score only most severe presentation.\nAlso see Specifications Table 6 for additional stipulations',1,''),(785,22,'PM4','ACMG summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: Considered as component of bioinformatic analysis (PP3/BP4).',0,''),(786,22,'PM5','ACMG summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nProtein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.\n\nInstructions:\nOnly applied to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). See Specifications Table 4, provided as a separate searchable excel file, for PM5_PTC codes applicable for predicted termination codon variants - organized by exon.',1,''),(787,22,'PM6','ACMG summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable\nComments: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.',0,''),(788,22,'PP1','ACMG summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\nApply weight as per Bayes Score:\nPP1_Very Strong - LR>350:1\nPP1_Strong - LR>18.7:1\nPP1_Moderate - LR>4.3:1\nPP1 - LR >2.08:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.\nStipulation: to apply code as Pathogenic Very Strong, VUS should have bioinformatically predicted (or experimentally proven) effect on protein or mRNA splicing. If co-segregation score is from a single family, or several families from an isolated population, assess the possibility of a different causative pathogenic variant.',1,''),(789,22,'PP2','ACMG summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: High frequency of benign missense variants.',0,''),(790,22,'PP3','ACMG summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nApply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.30). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.\nApply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.\nSee Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''),(791,22,'PP4','ACMG summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\n\nGene-specific modifications:\nBreast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4_Strong - LR>18.7:1\nPP4_Very Strong - LR>350:1\nPP4_Moderate - LR>4.3:1\nPP4 - LR >2.08:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\nSee Specifications Table7 and Appendix B for details.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''),(792,22,'PP5','ACMG summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.',0,''),(793,22,'BA1','ACMG summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nFilter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''),(794,22,'BS1','ACMG summary:\nAllele frequency is greater than expected for disorder.\n\nStrong:\nFilter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nSupporting\nFilter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.\n\nInstructions:\nApply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.\nDo not apply if read depth <20. Do not apply to well-established pathogenic founder variants.',1,''),(795,22,'BS2','ACMG summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nApplied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See Specifications Table 8 for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\nBS2 = ≥ 4 points\nBS2_Moderate = 2 points\nBS2_Supporting = 1 points\n\nInstructions:\nCo-occurrent P or LP variant should be assigned classification using VCEP specifications. \nSee Specifications Table 8 for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\nAlso see Specifications Table 8 for additional stipulations.',1,''),(796,22,'BS3','ACMG summary:\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\n\nGene-specific modifications:\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\nWell-established in vitro or in vivo functional studies supportive of no damaging effect as measured by effect on mRNA transcript profile (mRNA assay only). Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.\n\nInstructions:\nSee Specifications Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\nSee Specifications Table 9, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing.',1,''),(797,22,'BS4','ACMG summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nLack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\nBS4_VeryStrong - LR <0.00285:1\nBS4 - LR <0.05:1\nBS4_Moderate - LR <0.23:1\nBS4_Supporting - LR 0.23-0.48:1\n\nInstructions:\nRecommend use of online tool: https://fengbj-laboratory.org/cool3/analysis.html \nAdditional information, including pedigree formatting, is available at: https://fengbj-laboratory.org/cool3/manual.html.',1,''),(798,22,'BP1','ACMG summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\n\nGene-specific modifications\nApply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact. Missense prediction not applicable.',1,''),(799,22,'BP2','ACMG summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\nNot Applicable\nComments: Applied only in the context of BS2.',0,''),(800,22,'BP3','ACMG summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details',0,''),(801,22,'BP4','ACMG summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nMissense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.18 AND SpliceAI ≤0.1).\nSilent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).\nIntronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''),(802,22,'BP5','ACMG summary:\nVariant found in a case with an alternate molecular basis for disease.\n\nStrong\nUse ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5_VeryStrong - LR <0.00285:1\nBP5_Strong - LR <0.05:1\nBP5_Moderate - LR <0.23:1\nBP5 - LR 0.23-0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast-ovarian cancer risk genes have no specific phenotype.\n\nInstructions:\nUse in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\nSee Specifications Table7 for example application.',1,''),(803,22,'BP6','ACMG summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''),(804,22,'BP7','ACMG summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nStrong\nWell-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile - mRNA assay only. Apply as BP7_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.\n\nSupporting\nSilent variant inside a (potentially) clinically important functional domain, IF BP4 met.\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\nSee Specifications Figure1A and Appendix J for additional details.\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.\n\nInstructions:\nSee Specifications Figure 1B for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained. Not applicable for missense variants inside a (potentially) clinically important functional domain as they may still impact protein function through the amino acid change.\nFollowing convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI ≤0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. See Specifications Figure 1A for process to apply codes according to variant type, location and predicted bioinformatic impact.',1,''),(805,23,'PVS1','ACMG Summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nInstructions:\n - Use PALB2 PVS1 Decision Tree Per PALB2 Exon Map and PALB2 PVS1 Guide \n - PVS1: Predicted splice defect \n - PVS1_Strength(RNA): Observed splice defect \n - The default RefSeq transcript for nucleotide (c.) annotation is NM_024675.3/ENST00000261584.8. Several naturally occurring alternate splicing isoforms have been described. Yet, after careful examination, none of them is considered a candidate rescue transcript (very low contribution to overall expression, not coding proteins predicted functional, or both). In keeping with that, we have considered that all presumed LoF events (PVS1 decision tree specifications) occur in biologically relevant transcript(s).\n - WD40 beta propeller and the Coiled-coil domain (CC) are considered indispensable for PALB2 protein function. \n - PVS1 alterations that are predicted to escape NMD, but that adversely affect the WD40 domain can be granted PVS1 (as opposed to PVS1_Strong as the recommended baseline. The following evidence supports this strength change: \n - The WD40 domain interacts with many different protein partners that are involved in the double strand break repair pathway3\n - Two different C-terminal truncating mutations (c.3549C>A and c.3549C>G) resulting in loss of the last 3 amino acids [p.(Tyr1183Ter)], were identified in trans with PALB2 stop-gain variants in three unrelated FA (FA-N) patients4\n - The PALB2 WD40 toroidal structure is “sealed” in the seventh blade by interaction of the C-terminal strand with the incomplete N-terminal blade. The last four residues of PALB2 (Y1183, H1184, Y1185, and S1186) are directly involved in this interaction (molecular Velcro hydrogen bonding)00. This is the rationale for the clinical relevance of the last 4 amino acids of the protein.\n - Alterations predicted to lead to in frame losses adversely affecting the WD40 structure/function are found in trans with LoF PALB2 alterations in Fanconi Anemia patients4\n - Exon 10 donor: c.3113+5G>C (biallelic with c.395delT)\n - Exon 12 donor: c.3350+4A>G (biallelic with c.2393_2394insCT)\n - LoF alterations are rare in GnomAD in all exons\n - GnomAD v2.1 accessed 5/30/2019\n - Total Variants (includes splice acceptor/donor-conservative)\n - 1418 variants\n - 336,349 carriers\n - LoF Flag (excludes splice acceptor/donor-conservative)\n - 95 variants (6.7%)\n - 239 carriers (.07%)\n - PVS1 can be applied as per the PVS1 decision tree.\n - PVS1_Variable(RNA) shall be used for observed splice defects, whether from canonical +/-1,2 positions or other spliceogenic regions (including mid-exonic missense/synonymous variants that cause splice defects) with baseline weight as per the below decision tree. Weight can be further modified based on the quality of the RNA study including consideration of concepts such as:\n - Starting material (where patient material is preferable to in vitro minigene)\n - Use of NMD inhibitors where translation does occur such as cell lines56\n - Primer design (to make sure it\'s comprehensive to capture possible multicassette events)\n - Method of quantification \n - where e.g. capillary electrophoresis is preferable to estimation by gel band density\n - where SNP analysis is most preferred (where analysis of exonic SNPs and their relative presence in aberrant and WT transcripts is informative)\n - Quantification (where complete effects should have increased weight over incomplete effects)\n - Specific guidance on the use of RNA evidence in variant assessment is not a gene-specific consideration for PALB2 at this time, therefore discretion is left to assessors until further guidance is provided for this general concept from the Sequence Variant Interpretation group.',1,''),(806,23,'PS1','ACMG Summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nUse PALB2 PS1 Splicing table\n\nInstructions:\n - Protein: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2\n - RNA: See PALB2 PS1 Table \n - * Prerequisite for all: The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. \n - (Likely) pathogenic variant should be assigned classification using VCEP specifications. \n - For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the VUA and (likely) pathogenic variant should also be considered before application of this code. \n - Canonical dinucleotide refers to donor and acceptor dinucleotides in reference transcript/s used for curation. \n - Designated donor and acceptor site motifs ranges should be based on position weight matrices for intron category. \n - For GT-AG introns these are defined as follows: the donor site motif, last 3 bases of the exon and 6 nucleotides of intronic sequence adjacent to the exon; acceptor site motif, first base of the exon and 20 nucleotides upstream from the exon boundary. Consider other motif ranges for non GT-AG introns. \n - # If relevant, splicing data for a pathogenic variant outside a canonical dinucleotide may be used to update a PVS1 decision tree, and hence the applicable PVS1 code for a canonical dinucleotide variant.',1,''),(807,23,'PS2','ACMG Summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot Applicable\nComments: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase - Autosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified. - Autosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.',0,''),(808,23,'PS3','ACMG Summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\nNot Applicable\nComments: Protein: Do not use: Lack of known positive controls - RNA: Do not use: See code PVS1_Variable(RNA)',0,''),(810,23,'PM1','ACMG Summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable\nComments: Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.',0,''),(811,23,'PM2','ACMG Summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nVariant absent in gnomAD or present in <= 1/300,000 alleles\n\nInstructions:\n - PM2_supporting is not considered a conflicting piece of evidence for variants that otherwise are likely benign/benign \n - Use as PM2_Supporting (not moderate)',1,''),(812,23,'PM3','ACMG Summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nGene-specific modifications:\nUse Fanconi Anemia PM3 tables (See instructions below)\n\nInstructions:\nFanconi Anemia (FA) of any subtype is generally considered an exceedingly rare, severe, early-onset disease with variable features. In the case of BRCA2, hypomorphic FA patients have been described who are diagnosed at older ages with less severe phenotypes. The criteria set forth in the tables below are designed to accommodate such hypomorphs and are recommended to be applied to all FA-associated genes which may not be as well described due to the extreme infrequency of their identification, and due to ascertainment bias (for severe phenotype) in the literature.\nVariant may not exceed general population frequency >0.01%. Consider other gene panel test results as potential explanation for phenotype. \nMultiple unrelated cases are additive. \n - Ex. one individual homozygous for a variant with Fanconi gets 2.0 points. Another individual affected with Fanconi Anemia has the same variant and another truncating PALB2 variant with phase unknown gets 2.0 points. In total, there are 4.0 points towards PM3.\nPhenotype consistent: Chromosomal breakage with 1 clinical feature OR at least 2 of 3 clinical features from separate categories without chromosomal breakage studies\n - Ex. Chromosomal breakage testing + microcephaly / triangular face \n - Ex. (Without chromosomal breakage): Myelodysplastic Syndrome and microcephaly / triangular face. Individuals must have features from at least 2 of 3 distinct Cinical Feature categories below. \n - Positive for chromosome breakage test:\n - Increased chromosome breakage and/or radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) or mitomycin C (MMC)\n - Clinical features indicative of FA, including \n - Physical features (in ~75% of affected persons), include: \n - prenatal and/or postnatal short stature\n - abnormal skin pigmentation (e.g., café au lait macules, hypo- pigmentation)\n - Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)\n - Microcephaly, triangular face\n - Ophthalmic anomalies\n - Genitourinary tract anomalies.\n - See Orphanet 13 for full list of >100 HPO terms (and their reported frequency).\n - Pathology findings and laboratory findings (non-cancer related) include\n - progressive bone marrow failure (unrelated to cancer treatment)\n - aplastic anemia\n - Myelodysplastic syndrome\n - Inordinate toxicities from chemotherapy or radiation\n - macrocytosis\n - cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)\n - increased fetal hemoglobin (often precedes anemia). \n - Note: FA patients with very early onset cancer (<=5yr) may not present with hematologic disease, which is reported to have median age at onset of 7 years in FA patients in general14\n - Cancer diagnosis <=5yr, particularly\n - Blood cancers (AML)\n - Brain cancers (medulloblastoma, neuroblastoma)\n - Wilms Tumor\n\nSpecifications are adapted from definitions from GeneReviews (last revision June 3, 2021)',1,''),(813,23,'PM4','ACMG Summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: Do not use for in-frame deletions/insertions that are not already PVS1-eligible as no information is available to justify the application of this rule. - In addition, missense and small in-frame indels are not yet confirmed as a mechanism of disease for PALB2. - Do not use for stop-loss due to lack of data on stop-loss variants.',0,''),(814,23,'PM5','ACMG Summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nApply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*\n\nInstructions:\n - For protein: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.\n - Apply as PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*\n - Apply to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Tyr1183 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone',1,''),(815,23,'PM6','ACMG Summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable\nComments: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase',0,''),(816,23,'PP1','ACMG Summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications:\n\nStrong: LOD >=1.26 or Bayes Factor (LR) >=18:1\nModerate: LOD >=.60 or Bayes Factor (LR) >=4:1\nSupporting: LOD >=0.3 or Bayes Factor (LR) >=2:1\n\nInstructions:\n - AD Condition: use as per Co-Segregation Guidelines\n - AR Condition: informative instances of co-segregation in FANCN families are too rare to be considered for weight at this time. \n - Co-Segregation Guidelines\n - Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores9 using multiple phenotypes.\n - PP1_Strong: LOD >=1.26 or Bayes Factor (LR) >=18:1\n - PP1_Moderate: LOD >=.60 or Bayes Factor (LR) >=4:1\n - PP1: LOD >=0.3 or Bayes Factor (LR) >=2:18\n - BS4_Supporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n - BS4_Moderate: LOD <= -.64 or Bayes Factor (LR) <=.23\n - BS4: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\n - A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng\'s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1. Navigate to COOL (COsegregation OnLine)\n 2. Input \'PALB2\' into the \'Input a Gene Symbol\' field (the PALB2 defaults are approved by this VCEP)\n 3. Upload your Pedigree File (see COOL (COsegregation OnLine) manual for formatting)\n 4. Leave all defaults as is. Select \'Submit\' to obtain LR based on Full Likelihood Bayes (FLB)',1,''),(817,23,'PP2','ACMG Summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2',0,''),(818,23,'PP3','ACMG Summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\n - Protein: Do not use.\n - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n\nInstructions:\n - Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants\n - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n - NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n - NOTE: PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes.\n - Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.',1,''),(819,23,'PP4','ACMG Summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\nNot Applicable\nComments: Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. For AR disorder, use PM3 for specific phenotype considerations',0,''),(820,23,'PP5','ACMG Summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''),(821,23,'BA1','ACMG Summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nGnomAD Filtering Allele Frequency Allele frequency >0.1%\n\nInstructions:\nRounded from .118% established using Whiffin calculator:\n - Prevalence (breast cancer): 1:8\n - Allelic Heterogeneity: 1 (differs from BS1)\n - Genetic Heterogeneity: .01\n - Penetrance: .53',1,''),(822,23,'BS1','ACMG Summary:\nAllele frequency is greater than expected for disorder.\n\nGene-specific modifications:\nGnomAD Filtering Allele Frequency greater than expected for disease >.01%\n\nInstructions:\n - Rounded from .0118% established using Whiffin calculator: \n - Prevalence (breast cancer): 8 \n - Allelic Heterogeneity: 0.1 (differs from BA1) \n - Genetic Heterogeneity: .01 \n - Penetrance: .53',1,''),(823,23,'BS2','ACMG Summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nPer Fanconi Anemia BS2 tables\n\nInstructions:\n See Fanconi Anemia BS2 tables\n Do not use for individuals in population based cohorts, such as gnomAD \n Consider multiple instances of co-occurrence with the same variant are more likely to be in cis in unrelated individuals when assessing BS2 application',1,''),(824,23,'BS3','Original ACMG Summary\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\nNot Applicable\nComments: - Do not use: Protein functional studies (BS3) See PS3 for details - RNA functional studies (Use BP7_Variable(RNA))',0,''),(825,23,'BS4','ACMG Summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nStrong: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\nModerate: LOD <= -.64 or Bayes Factor (LR) <=.23\nSupporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n\nInstructions:\n - Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores9 using multiple phenotypes. \n - PP1_Strong: LOD >=1.26 or Bayes Factor (LR) >=18:1 \n - PP1_Moderate: LOD >=.60 or Bayes Factor (LR) >=4:1\n - PP1: LOD >=0.3 or Bayes Factor (LR) >=2:1\n - BS4_Supporting: LOD <=-.32 or Bayes Factor (LR) <=.48\n - BS4_Moderate: LOD <= -.64 or Bayes Factor (LR) <=.23\n - BS4: LOD <= -1.28 or Bayes Factor (LR) LR<=.053:1\n - A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng\'s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1. Navigate to COOL (COsegregation OnLine)11\n 2. Input \'PALB2\' into the \'Input a Gene Symbol\' field (the PALB2 defaults are approved by this VCEP)\n 3. Upload your Pedigree File (see COOL (COsegregation OnLine) manual12 for formatting)\n 4. Leave all defaults as is. Select \'Submit\' to obtain LR based on Full Likelihood Bayes (FLB)',1,''),(826,23,'BP1','ACMG Summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\n\nGene-specific modifications:\nApply to all missense variants.\n\nInstructions:\nBased on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2.',1,''),(827,23,'BP2','ACMG Summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\nNot Applicable\nComments: Do not use: See Fanconi Anemia BS2 table',0,''),(828,23,'BP3','ACMG Summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function',0,''),(829,23,'BP4','ACMG Summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\nNot Applicable\nComments: - Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants - RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing o NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) o NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect) o Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.',0,''),(830,23,'BP5','ACMG Summary:\nVariant found in a case with an alternate molecular basis for disease.\nNot Applicable\nComments: Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.',0,''),(831,23,'BP6','ACMG Summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''),(832,23,'BP7','ACMG Summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nGene-specific modifications:\nStrong:\n - BP7_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality.\n\nModerate:\n - BP7_Variable(RNA):Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality\n\nSupporting:\n - BP7: Synonymous and deep intronic\n - BP7_Variable(RNA): Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality\n\nInstructions:\n - BP7: Synonymous and deep intronic\n - Can be used for deep intronic variants beyond (but not including) +7 (donor) and -21 (acceptor)\n - May also apply BP4 to achieve Likely Benign\n - Is not considered a conflicting piece of evidence against a body of evidence supporting a pathogenic splice defect\n - BP7_Variable(RNA): RNA functional studies\n - Lack of aberrant splice defect: Please see PVS1_Variable(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays\n - NOTE: BP4 splice predictions may not be used in conjunction with BP7',1,''),(833,24,'PVS1','ACMG Summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nDefer to SVI recommendations',1,''),(834,24,'PS1','ACMG Summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nStrong:\nMust confirm there is no difference in splicing using RNA data. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.\n\nModerate:\nMust confirm there is no difference in splicing using in silico modeling data using a splice metapredictor (SpliceAI, VarSEAK, etc). Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.\n\nInstructions:\nCan only compare to variants asserted as payhogenic by the ClinGen TP53 VCEP',1,''),(835,24,'PS2','ACMG Summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\n\nGene-specific modifications:\nUse SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.\n\nVery Strong: ≥4 points (ex. - 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.\nStrong: 2-3 points (ex. - 1 cancer from the strong criteria list or 2 from the moderate criteria list)\nModerate: 1 point (for 1 cancer from the moderate criteria list)\nSupporting: 0.5 point (1 cancer from the moderate criteria list)\n\nInstructions:\nUse SVI point system table',1,''),(836,24,'PS3','ACMG Summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\n\nGene-specific modifications:\nStrong:\nTransactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a low functioning allele (<= 20% activity) AND:\n Evidence of dominant negative effect (DNE) + evidence of LOF from Giacomelli, et al data OR\n There is a 2nd assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays) Do not use code with conflicting evidence\n\n\nModerate:\n(A) Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20-and <=75% activity) AND:\n Evidence of DNE + evidence of LOF from Giacomelli, et al data. OR\n There is a 2nd assay showing low function. Do not use code with conflicting evidence. (B) No transactivation assays (IARC classification based on data Kato et al, 2003) available BUT:\n Evidence of DNE + evidence of LOF from Giacomelli, et al data. AND\n There is a 2nd assay showing low function Do not use code with conflicting evidence.\n\nInstructions:\nSee flow chart for use of Kato, Giacomelli, and Kotler assays. Non-systematic assays are harder to interpret but if there are several of them and if all suggets benign or pathogenic, they should be taken into account. A large proportion of these assays are documented in the IARC database and should be easily found by curtators. Other assays that may be used including in vitro growth asaays in H1299 human cells from Kotler et al (2018) with RFS score >= -1.0 for LOF and RFS score <1 for noLOF; or colony formation assays, growth suppression assays, apoptosis assays, tetramer assays, knock-in mouse models. Do not use code with conflicting evidence.',1,''),(837,24,'PS4','ACMG Summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nUse proband counting system described below in text.\n\nPS4 = 4+ points\nPS4_moderate = 2-3 points\nPS4_Suppporting = 1 point\n\nInstructions:\nUse proband counting system',1,''),(838,24,'PM1','ACMG Summary\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\n\nGene-specific modifications:\nThis rule can be applied to variants in hot spots (codons 175, 245, 248, 249, 273, 282), but not to variants within functional domains. Use transcript NM_000546.4. Also use rule for variants with ≥10 somatic observations cancerhotspots.org (v2)',1,''),(839,24,'PM2','ACMG Summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nVariant needs to be absent from controls. The variant must be absent from population databases. gnomAD is the preferred population database at this time (http://gnomad.broadinstitute.org). The most recent version of gnomAD with a non-cancer subpopulation should be used; however, other versions may be utilized if there is reason to believe they would provide necessary information for curating the variant.\nModification Type: Disease-specific,General recommendation\n\nInstructions:\nThe variant must be absent from population databases, gnomAD is the preferred pipulation database at this time.',1,''),(840,24,'PM3','ACMG Summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\nNot Applicable\nComments: This rule does not apply to TP53/Li_Fraumeni syndrome.',0,''),(841,24,'PM4','ACMG Summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\nNot Applicable\nComments: This rule should not be used at this time due to limited data.',0,''),(842,24,'PM5','ACMG Summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nModerate:\nMultiple pathogenic variants (≥2) at that residue using the requirements specified below (excluding known hot spots) would be required. Grantham should be used to compare the variants. At least one of the new variants must be equal or worse than known pathogenic variant. Splicing should be ruled out. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP. Rule cannot be used in conjunction with PM1.\n\nSupporting:\nGrantham should be used to compare variants. The new variant must be equal or worse than known mutation. Splicing should be ruled out. Rule cannot be used in conjunction with PM1.\n\nInstructions:\nThis evidence code can be applied when there are >2 pathogenic variants at the same residue (excluding known hot spots). The other variants must be asserted as pathogenic by the ClinGen TP53 VCEP. Grantham should be used to compare the variants. The variant being evaluated must be equal to or worse than known mutations. Splicing should be ruled out.',1,''),(843,24,'PM6','ACMG Summary:\nAssumed de novo, but without confirmation of paternity and maternity.\n\nGene-specific modifications:\nUse SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.\n\nVery Strong: ≥4 points (ex. - 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.\nStrong: 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)\nModerate: 1 point (for 1 cancer from the moderate criteria list)\nSupporting: 0.5 point (1 cancer from the moderate criteria list)\n\nInstructions:\nSee above for PS2_PM6 combined rule',1,''),(844,24,'PP1','ACMG Summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\n\nGene-specific modifications:\nCosegregation must be observed in...\nStrong: ≥7 meioses in >1 family\nModerate: 5-6 meioses in 1 family\nSupporting: 3-4 meioses in 1 family\nto apply this rule',1,''),(845,24,'PP2','Original ACMG Summary\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable\nComments: This rule does not apply due to the high number of benign missense variation.',0,''),(846,24,'PP3','ACMG Summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nModerate:\nPolyPhen2 and SIFT in silico modeling programs should not be used for this gene. Missense variants: aGVGD (Zebrafish; Class C65 required) and BayesDel (score ≥ 0.16)\n\nSupporting:\nPolyPhen2 and SIFT in silico modeling programs should not be used for this gene. Concordance of two predictors is recommended for this gene:\n - Missense variants: aGVGD (Zebrafish; Class C25 and higher are considered evidence of pathogenicity) and BayesDel (scores ≥ 0.16 are considered evidence of pathogenic)\n - Splicing variants: Evidence of splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).\n\nInstructions:\nConcordance of two predictors is recommended for this gene. Missense variants: according to a published study by Fortuno et al 2018 comparing the performance of different bioinformatics tools for TP563, the tools selected are aGVGD (Zebrafish; Class C15 and higher are considered evidence of pathogenicity) and BayesDel (scores >=0.16 are considered evidence of pathogenic). Please refer to the cited manuscript for further details. Splicing variants: MaxEntScan and Human Splicing Finder (HSF) should be used.',1,''),(847,24,'PP4','Original ACMG Summary\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\n\nGene-specific modifications:\nUse modified PS4 criteria instead of PP4 code.',1,''),(848,24,'PP5','ACMG Summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''),(849,24,'BA1','ACMG Summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nGene-specific modifications:\nFrequency cutoff of 0.1% minimum of 5 alleles present in the population\n\nInstructions:\nUse a minor allele frequency cutoff of >=0.001 or 0.1% (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on Wiffen-Ware calculator.',1,''),(850,24,'BS1','ACMG Summary:\nAllele frequency is greater than expected for disorder.\n\nGene-specific modifications:\nFrequency cutoff of 0.03%; minimum of 5 alleles present in the population.\n - Use a minor allele frequency cutoff of >0.0003 but <0.001 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator.\n - To set the strong benign MAF cutoff, we used a prevalence of 1 in 5,000 from Lalloo, et a 2006 (PMID:16644204). We set the genetic and allelic heterogeneity at 100% and penetrance at 30%.\n\nInstructions:\nUse a minor allele frequency cutoff of >=0.0003 but <0.001 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on Whiffen-Ware calculator.',1,''),(851,24,'BS2','ACMG Summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\n\nGene-specific modifications:\nStrong:\nObserved in ≥8 cancer free 60+ year old females obtained from the same data source. Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:\n - This evidence code can be used when a variant is observed in ≥8 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.\n\nSupporting:\nObserved in 2-7 cancer free 60+ year old females obtained from the same data source. Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:\n - This evidence code can be used when a variant is observed in 2-7 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.',1,''),(852,24,'BS3','ACMG Summary:\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\n\nGene-specific modifications:\n\nStrong:\nTransactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that show retained function (76-140% activity) or supertransactivation function AND:\n - No evidence of DNE + no evidence of LOF from Giacomelli, et al data. OR There is a 2nd assay, including colony formation assays, apoptosis assays, tetramer assays, growth suppression and knock-in mouse models demonstrating retained function. Do not use code with conflicting evidence\n \nSupporting:\nTransactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <=75% activity) AND:\n-_No evidence of DNE + no evidence of LOF from Giacomelli, et al data. OR\n - There is a 2nd assay demonstrating retained function Do not use code with conflicting evidence. No transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) available BUT:\n - No evidence of DNE + no evidence of LOF from Giacomelli, et al data. AND There is a 2nd assay showing retained function Do not use code with conflicting evidence',1,''),(853,24,'BS4','ACMG Summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\n\nGene-specific modifications:\nVariant segregates to opposite side of the family who meets LFS criteria. OR Variant is present in ≥3 living unaffected individuals (at least 2 of which should be female) above 55 years of age.\n\nInstructions:\nEvidence code can be used in either scenario: the variant segregates to the opposite side of the family who meets LFS criteria OR the variant is present in >=3 living unaffected individuals ( at least 2 of 3 should be female) above 55 years of age',1,''),(854,24,'BP1','ACMG Summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\nNot Applicable\nComments: This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants.',0,''),(855,24,'BP2','ACMG Summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\n\nGene-specific modifications:\nThis evidence code can be applied in either scenario below:\n - Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed), or\n - When there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two different pathogenic/likely pathogenic TP53 variants.\n\nInstructions:\nEvidence code can be applied in either scenario: Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed) OR when there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two differemt pathogenic or likely pathogenic TP53 variants.',1,''),(856,24,'BP3','ACMG Summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable\nComments: Do not use this rule at this time.',0,''),(857,24,'BP4','ACMG Summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\nMissense: aGVGD (zebrafish; Class C0 or C15 is considered evidence of non-pathogenicity) and BayesDel <0.16 is considered evidence on non-pathogenicity Splicing: Evidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).\n\nInstructions:\nConcordance of two predictors is recommended for this gene. Missense variants: according to a published study by Fortuno et al 2018 comparing the performance of different bioinformatics tools for TP53, the tools selected are aGVGD (Zebrafish; Class C0 or C15 is considered evidence of non-pathogenicity_ and BayesDel <0.16 is considered evidence of non-pathogenicity). Splicing variants: MaxEntScan and Human Splicing Finder (HSF)',1,''),(858,24,'BP5','ACMG Summary:\nVariant found in a case with an alternate molecular basis for disease.\nNot Applicable\nComments: This rule code is not recommended for use at this time.',0,''),(859,24,'BP6','ACMG Summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ',0,''),(860,24,'BP7','ACMG Summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nGene-specific modifications:\nEvidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc). If a new alternate site is predicted, compare strength to native site in interpretation.\n\nInstructions:\nConcordance of MaxEntScan and Human Splice Finder are required to use this evidence code. If an alternate site is predicted, comapre strength to native site in interpretation',1,''),(1089,23,'PS4','ACMG Summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nCase-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=3 OR lower 95% CI >=1.5).\n\nInstructions:\nPS4_Moderate: Do not use. Proband counting for genes causing a common disorder need to be calibrated in a population-specific way before use.',1,''),(1281,28,'PVS1','Original ACMG Summary:\nNull variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n - Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n - Use caution interpreting LOF variants at the extreme 3\' end of a gene.\n - Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n - Use caution in the presence of multiple transcripts.\n\nGene-specific modifications:\nUse ATM PVS1 Decision Tree.',1,''),(1282,28,'PS1','Original ACMG Summary:\nSame amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nStrong:\nUse for protein changes as long as splicing is ruled-out for both alterations.\n\nModerate:\nUse for RNA changes as code PS1_RNA_Moderate if predictions or observations are similar or worse for the variant under consideration. Close matches must be VCEP approved LP/P variants.\n\nInstructions:\nUse as ascribed for protein changes as long as a splice defect is ruled out for both variants; Use as PS1_RNA_Moderate for close-match splicing variants with similar predictions or observations of splice defect. Close matches must be VCEP approved as LP/P.',1,''),(1283,28,'PS2','Original ACMG Summary:\nDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\nNot Applicable',0,''),(1284,28,'PS3','Original ACMG Summary:\nWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.\n\nGene-specific modifications:\nStrong:\nDo not use as strong.\n\nModerate:\nUse when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.\n\nSupporting:\nUse when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency\n\nInstructions:\nFor protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion).',1,''),(1285,28,'PS4','Original ACMG Summary:\nThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nGene-specific modifications:\nStrong:\nUse for case control studies that reflect an OR ≥2, p≤.05 and lower 95% CI ≥1.5.\n\nModerate:\nDo not use for proband counting.\n\nInstructions:\nDo not use for \'proband counting\' method. Use for case control studies that reflect an OR ≥2, p≤.05 and lower 95% CI ≥1.5.',1,''),(1286,28,'PM1','Original ACMG Summary:\nLocated in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\nNot Applicable',0,''),(1287,28,'PM2','Original ACMG Summary:\nAbsent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.\n\nGene-specific modifications:\nFrequency ≤.001% when N>1 in a large general population database (e.g. gnomAD 2.1.1)\n\nInstructions:\nUse as PM2_Supporting for variants with a general population frequency ≤.001% in all sub-populations when N>1.',1,''),(1288,28,'PM3','Original ACMG Summary:\nFor recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.\n\nInstructions:\nUse ATM PM3/BP2 table.',1,''),(1289,28,'PM4','Original ACMG Summary:\nProtein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\nGene-specific modifications:\nUse for stop-loss variants.\n\nInstructions:\nDo not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.',1,''),(1290,28,'PM5','Original ACMG Summary:\nNovel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nGene-specific modifications:\nUse for genomic frameshift and truncating variants with PTC upstream of p.R3047. Do not use for splice or start-loss variants\n\nInstructions:\nDo not use for \'hotspot\'. Can be used for genomic frameshift and truncating variants with PTC upstream of p.R3047 as PM5_Supporting.',1,''),(1291,28,'PM6','Original ACMG Summary:\nAssumed de novo, but without confirmation of paternity and maternity.\nNot Applicable',0,''),(1292,28,'PP1','Original ACMG Summary:\nCo-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.\nNot Applicable\nComments: Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available.',0,''),(1293,28,'PP2','Original ACMG Summary:\nMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.\nNot Applicable',0,''),(1294,28,'PP3','Original ACMG Summary:\nMultiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.\n\nInstructions:\nProtein: REVEL >.7333; RNA: multiple in silico predictors agree to a similar effect.',1,''),(1295,28,'PP4','Original ACMG Summary:\nPatient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.\nNot Applicable',0,''),(1296,28,'PP5','Original ACMG Summary:\nReputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.',0,''),(1297,28,'BA1','Original ACMG Summary:\nAllele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\n\nInstructions:\nFiltering Allele Frequency >.5%.',1,''),(1298,28,'BS1','Original ACMG Summary:\nAllele frequency is greater than expected for disorder.\n\nInstructions:\nFiltering Allele Frequency >.05%.',1,''),(1299,28,'BS2','Original ACMG Summary:\nObserved in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.\nNot Applicable',0,''),(1300,28,'BS3','Original ACMG Summary:\nWell-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.\n\nGene-specific modifications:\nModerate:\nUse when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.\n\nSupporting:\nUse when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.\n\nInstructions:\nFor protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion).',1,''),(1301,28,'BS4','Original ACMG Summary:\nLack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.\nNot Applicable\nComments: AD Condition: Co-segregation analysis in lowpenetrance genes can lead to false positive results (PMID 32773770) . AR Condition: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.',0,''),(1302,28,'BP1','Original ACMG Summary:\nMissense variant in a gene for which primarily truncating variants are known to cause disease.\nNot Applicable',0,''),(1303,28,'BP2','Original ACMG Summary:\nObserved in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.\n\nInstructions:\nUse ATM PM3/BP2 table.',1,''),(1304,28,'BP3','Original ACMG Summary:\nIn frame-deletions/insertions in a repetitive region without a known function.\nNot Applicable',0,''),(1305,28,'BP4','Original ACMG Summary:\nMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.\n\nGene-specific modifications:\n Protein Analysis: Metapredictor REVEL score ≤.249\n RNA Analysis: Concordance of ≥2 predictors reflecting no predicted splice defect\n NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects)\n NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_O_Variable (a lack of observed RNA defect)\n NOTE: BP4 for protein predictors may be applied to BS3_Variable for protein effects. \n NOTE: BP4 could be used towards an RNA impact, a protein impact or both, as applicable. However, a variant\'s classification should be the sum of evidence for RNA or protein as tallied independently and should not mix-and-match evidence from RNA and protein evidence bodies. \n Example: Do not apply BP4 for in silico splice predictions toward the classification of a missense variant where all other evidence points towards a benign protein effect (instead apply PP3 or BP4, as applicable, for a protein predictor).\n\nInstructions:\nProtein: REVEL <.249; RNA: multiple in silico predictors agree to a lack of splice defect.',1,''),(1306,28,'BP5','Original ACMG Summary:\nVariant found in a case with an alternate molecular basis for disease.\nNot Applicable',0,''),(1307,28,'BP6','Original ACMG Summary:\nReputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.\nNot Applicable\nThis criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.',0,''),(1308,28,'BP7','Original ACMG Summary:\nA synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\nGene-specific modifications:\nStrong/Moderate:\nCan be considered for BP7_O with curator discretion of quality.\n\nSupporting:\nCan be considered for BP7_O with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively\n\nInstructions:\nUse for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively. Use as BP7_O for synonymous and intronic variants with no splice defect observed. Weight for BP7_O is variable based on curator impression fo assay quality (not specified).',1,''),(1335,30,'PVS1','Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease \n\nCaveats: \n- Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7) \n- Use caution interpreting LOF variants at the extreme 3\' end of a gene \n- Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact \n- Use caution in the presence of multiple transcripts',1,''),(1336,30,'PS1','Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. \n\nExample: Val->Leu caused by either G>C or G>T in the same codon \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level',1,''),(1337,30,'PS2','De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. \n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.',1,''),(1338,30,'PS3','Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. \n\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.',1,''),(1339,30,'PS4','The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. \n\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. \n\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.',1,''),(1340,30,'PM1','Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.',1,''),(1341,30,'PM2','Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC. \n\nCaveat: Population data for indels may be poorly called by next generation sequencing.',1,''),(1342,30,'PM3','For recessive disorders, detected in trans with a pathogenic variant. \n\nNote: This requires testing of parents (or offspring) to determine phase.',1,''),(1343,30,'PM4','Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.',1,''),(1344,30,'PM5','Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. \n\nExample: Arg156His is pathogenic; now you observe Arg156Cys. \nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.',1,''),(1345,30,'PM6','Assumed de novo, but without confirmation of paternity and maternity.',1,''),(1346,30,'PP1','Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\nNote: May be used as stronger evidence with increasing segregation data.',1,''),(1347,30,'PP2','Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.',1,''),(1348,30,'PP3','Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.',1,''),(1349,30,'PP4','Patient\'s phenotype or family history is highly specific for a disease with a single genetic etiology.',1,''),(1350,30,'BA1','Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC.',1,''),(1351,30,'BS1','Allele frequency is greater than expected for disorder.',1,''),(1352,30,'BS2','Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.',1,''),(1353,30,'BS3','Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.',1,''),(1354,30,'BS4','Lack of segregation in affected members of a family. \n\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.',1,''),(1355,30,'BP1','Missense variant in a gene for which primarily truncating variants are known to cause disease',1,''),(1356,30,'BP2','Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.',1,''),(1357,30,'BP3','In-frame deletions/insertions in a repetitive region without a known function',1,''),(1358,30,'BP4','Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) \n\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.',1,''),(1359,30,'BP5','Variant found in a case with an alternate molecular basis for disease.',1,''),(1360,30,'BP7','A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.',1,''); UNLOCK TABLES; -- @@ -519,928 +87,24 @@ UNLOCK TABLES; -- LOCK TABLES `classification_criterium_strength` WRITE; -INSERT INTO `classification_criterium_strength` (`id`,`classification_criterium_id`,`name`,`display_name`,`description`,`is_default`) VALUES -(1,1,'pvs','vstr','very strong pathogenic',1), -(2,1,'ps','str','strong pathogenic',0), -(3,1,'pm','mod','medium pathogenic',0), -(4,1,'pp','sup','supporting pathogenic',0), -(5,2,'pvs','vstr','very strong pathogenic',0), -(6,2,'ps','str','strong pathogenic',1), -(7,2,'pm','mod','medium pathogenic',0), -(8,2,'pp','sup','supporting pathogenic',0), -(9,3,'pvs','vstr','very strong pathogenic',0), -(10,3,'ps','str','strong pathogenic',1), -(11,3,'pm','mod','medium pathogenic',0), -(12,3,'pp','sup','supporting pathogenic',0), -(13,4,'pvs','vstr','very strong pathogenic',0), -(14,4,'ps','str','strong pathogenic',1), -(15,4,'pm','mod','medium pathogenic',0), -(16,4,'pp','sup','supporting pathogenic',0), -(17,5,'pvs','vstr','very strong pathogenic',0), -(18,5,'ps','str','strong pathogenic',1), -(19,5,'pm','mod','medium pathogenic',0), -(20,5,'pp','sup','supporting pathogenic',0), -(21,6,'pvs','vstr','very strong pathogenic',0), -(22,6,'ps','str','strong pathogenic',0), -(23,6,'pm','mod','medium pathogenic',1), -(24,6,'pp','sup','supporting pathogenic',0), -(25,7,'pvs','vstr','very strong pathogenic',0), -(26,7,'ps','str','strong pathogenic',0), -(27,7,'pm','mod','medium pathogenic',1), -(28,7,'pp','sup','supporting pathogenic',0), -(29,8,'pvs','vstr','very strong pathogenic',0), -(30,8,'ps','str','strong pathogenic',0), 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pathogenic',0),(2876,1347,'pp','sup','supporting pathogenic',1),(2877,1348,'pvs','vstr','very strong pathogenic',0),(2878,1348,'ps','str','strong pathogenic',0),(2879,1348,'pm','mod','medium pathogenic',0),(2880,1348,'pp','sup','supporting pathogenic',1),(2881,1349,'pvs','vstr','very strong pathogenic',0),(2882,1349,'ps','str','strong pathogenic',0),(2883,1349,'pm','mod','medium pathogenic',0),(2884,1349,'pp','sup','supporting pathogenic',1),(2885,1350,'ba','alo','stand-alone benign',1),(2886,1350,'bs','str','strong benign',0),(2887,1350,'bp','sup','supporting benign',0),(2888,1351,'ba','alo','stand-alone benign',0),(2889,1351,'bs','str','strong benign',1),(2890,1351,'bp','sup','supporting benign',0),(2891,1352,'ba','alo','stand-alone benign',0),(2892,1352,'bs','str','strong benign',1),(2893,1352,'bp','sup','supporting benign',0),(2894,1353,'ba','alo','stand-alone benign',0),(2895,1353,'bs','str','strong benign',1),(2896,1353,'bp','sup','supporting benign',0),(2897,1354,'ba','alo','stand-alone benign',0),(2898,1354,'bs','str','strong benign',1),(2899,1354,'bp','sup','supporting benign',0),(2900,1355,'ba','alo','stand-alone benign',0),(2901,1355,'bs','str','strong benign',0),(2902,1355,'bp','sup','supporting benign',1),(2903,1356,'ba','alo','stand-alone benign',0),(2904,1356,'bs','str','strong benign',0),(2905,1356,'bp','sup','supporting benign',1),(2906,1357,'ba','alo','stand-alone benign',0),(2907,1357,'bs','str','strong benign',0),(2908,1357,'bp','sup','supporting benign',1),(2909,1358,'ba','alo','stand-alone benign',0),(2910,1358,'bs','str','strong benign',0),(2911,1358,'bp','sup','supporting benign',1),(2912,1359,'ba','alo','stand-alone benign',0),(2913,1359,'bs','str','strong benign',0),(2914,1359,'bp','sup','supporting benign',1),(2915,1360,'ba','alo','stand-alone benign',0),(2916,1360,'bs','str','strong benign',0),(2917,1360,'bp','sup','supporting benign',1),(3162,17,'ba','alo','stand-alone benign',1),(3163,17,'bs','str','strong benign',0),(3164,17,'bp','sup','supporting benign',0),(3177,22,'ba','alo','stand-alone benign',0),(3204,778,'pp','sup','supporting pathogenic',0); UNLOCK TABLES; - - +-- +-- Dumping data for table `mutually_exclusive_criteria` +-- LOCK TABLES `mutually_exclusive_criteria` WRITE; -INSERT INTO `mutually_exclusive_criteria` (`id`,`source`,`target`) VALUES (122,12,21),(123,17,5),(124,18,5),(125,21,12),(5,40,49),(8,45,33),(6,46,61),(7,49,40),(11,73,61),(9,74,61),(10,77,68),(12,93,100),(13,105,100),(14,106,100),(15,126,133),(16,138,133),(88,749,762),(89,762,749),(86,777,790),(87,790,777),(72,861,874),(73,874,861),(90,1320,1328),(91,1324,1313),(92,1325,1313),(93,1328,1320),(118,1346,1354),(119,1350,1339),(120,1351,1339),(121,1354,1346); +INSERT INTO `mutually_exclusive_criteria` VALUES (122,12,21),(123,17,5),(124,18,5),(125,21,12),(5,40,49),(8,45,33),(6,46,61),(7,49,40),(11,73,61),(9,74,61),(10,77,68),(12,93,100),(13,105,100),(14,106,100),(15,126,133),(16,138,133),(133,749,762),(134,762,749),(126,777,790),(127,790,777),(139,1346,1354),(140,1350,1339),(141,1351,1339),(142,1354,1346); UNLOCK TABLES; - - +-- +-- Dumping data for table `mutually_inclusive_criteria` +-- +LOCK TABLES `mutually_inclusive_criteria` WRITE; +INSERT INTO `mutually_inclusive_criteria` VALUES (3,749,758); +UNLOCK TABLES; -- @@ -1952,7 +616,9 @@ INSERT INTO `user_classification` VALUES (20,'5',15,3,'reha24365','2022-10-18 00:00:00',3,1,NULL), (26,'3',52,3,'this is a comment with\\tpecial characters','2022-10-06 06:00:00',2,1,NULL), (28,'3',15,3,'dsvsagbruj','2022-10-17 08:00:00',1,1,NULL), - (29,'5',15,3,'zterjdkzfrkfrk','2022-10-17 09:00:00',5,5,NULL); + (29,'5',15,3,'zterjdkzfrkfrk','2022-10-17 09:00:00',5,5,NULL), + (30,'5',168,3,'testclassification to delete','2022-10-17 09:00:00',5,5,NULL), + (31,'5',168,4,'testclassification unable to delete','2022-10-17 09:00:00',5,5,NULL); UNLOCK TABLES; @@ -1967,7 +633,9 @@ INSERT INTO `user_classification_criteria_applied` VALUES (10,11,12,17,'fasfd',1), (11,29,113,143,'fdhsjj\\srjerssb \\/x shzwsh\r\n wh ',1), (12,20,32,45,'qwerqwr',1), - (14,11,8,11,'ewqrqfr',1); + (14,11,8,11,'ewqrqfr',1), + (15,30,8,11,'ewqrqfr',1), + (16,31,8,11,'ewqrqfr',1); UNLOCK TABLES; @@ -1999,7 +667,7 @@ INSERT INTO `variant_heredicare_annotation` (`id`,`variant_id`,`vid`,`n_fam`,`n_ INSERT INTO `automatic_classification` VALUES - (1,52,'acmg-svi','2','3','2023-11-28 14:41:20','0.1.0'); + (1,52,30,'2','3','2023-11-28 14:41:20','0.1.0'); INSERT INTO `automatic_classification_criteria_applied` VALUES (108,1,'PVS1','general','pathogenic',1,'very_strong','','comment for criterium'); diff --git a/src/frontend_celery/tests/data/variant_52.vcf b/src/frontend_celery/tests/data/variant_52.vcf index 3484b4b6..2608cde3 100644 --- a/src/frontend_celery/tests/data/variant_52.vcf +++ b/src/frontend_celery/tests/data/variant_52.vcf @@ -1,5 +1,5 @@ ##fileformat=VCFv4.2 -##fileDate=2023-12-19 +##fileDate=2023-12-21 ##reference=GRCh38 ##INFO= ##INFO= @@ -33,4 +33,4 @@ ##INFO= ##INFO= #CHROM POS ID REF ALT QUAL FILTER INFO -chr13 32314943 52 A G . . phylop_100way=-0.021;cadd_scaled=7.930;spliceai_details=ZAR1L%7C0.00%7C0.00%7C0.02%7C0.00%7C31%7C-39%7C-44%7C32;spliceai_max_delta=0.02;gnomad_ac=5753;gnomad_af=0.0378129;gnomad_hom=353;gnomad_het=5047;gnomad_popmax=afr;gnomad_popmax_AF=0.131678;brca_exchange_clinical_significance=Benign_/_Little_Clinical_Significance;task_force_protein_domain=C-terminal_RAD51_binding_domain_(inkl._NLS1_und_BRC-)_;task_force_protein_domain_source=BWRL/ENIGMA;hexplorer=-5.12;hexplorer_mut=-4.84;hexplorer_wt=0.28;hexplorer_rev=4.56;hexplorer_rev_mut=-1.44;hexplorer_rev_wt=-6.00;heredicare_vid=11740058;clinvar=blimblam2;user_classification=3|this_is_a_comment_with\tpecial_characters|2022-10-06_06:00:00|ACMG_standard|-|PS1+very_strong_pathogenic+evidence1+1$PS2+strong_pathogenic+evidence2+1$PP1+very_strong_pathogenic+evidence3+1|;consensus_classification=5|A_random_test_classification|2022-09-07_03:00:00|ACMG_standard|3|PS1+supporting_pathogenic+ev1+1$PS2+strong_pathogenic+ev2+1$PS1+very_strong_pathogenic+ev3+1|;automatic_classification=3|2|2023-11-28_14:41:20|acmg-svi|PVS1+very_strong+comment_for_criterium+1+general;variation_id=209597;clinvar_summary=reviewed_by_expert_panel:Benign;clinvar_submissions=Benign|2015-01-12|reviewed_by_expert_panel|C2675520:Breast-ovarian_cancer,_familial_2|Evidence-based_Network_for_the_Interpretation_of_Germline_Mutant_Alleles_(ENIGMA)|description:_Class_1_not_pathogenic_based_on_frequency_>1%_in_an_outbred_sampleset._Frequency_0.14_(African),_derived_from_1000_genomes_(2012-04-30).;heredicare_annotation=12345|10|11|15|This_is_a_comment_from_heredicare|2019-08-17;consequences=ENST00000345108|None|None|upstream_gene_variant|modifier|None|None|ZAR1L|None|True|False|False|False|protein_coding|962&ENST00000380152|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|True|True|False|True|protein_coding|10231&ENST00000530893|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|True|False|False|False|protein_coding|9864&ENST00000533490|c.-390%2B372T>C|None|intron_variant|modifier|None|1|ZAR1L|None|True|True|False|True|protein_coding|962&ENST00000544455|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|True|False|False|False|protein_coding|10231&ENST00000614259|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|False|False|False|False|nonsense_mediated_decay|7934&ENST00000680887|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|False|False|False|False|protein_coding|10231&ENSR00000060894|None|None|regulatory_region_variant|modifier|None|None|None|None|False|False|False|False|None|None&ENSM00526233310|None|None|TF_binding_site_variant|modifier|None|None|None|None|False|False|False|False|None|None&ENSM00522614247|None|None|TF_binding_site_variant|modifier|None|None|None|None|False|False|False|False|None|None&NM_000059|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|True|True|False|True|mRNA|10231&NM_001136571|c.-390%2B372T>C|None|intron_variant|modifier|None|1|ZAR1L|None|True|True|False|True|mRNA|962;assays=2022-08-08|functional|12345.0&2022-08-09|functional|6565.0&2022-08-09|splicing|3654.0;literature=9425226&15342711&16333312&25994375 +chr13 32314943 52 A G . . phylop_100way=-0.021;cadd_scaled=7.930;spliceai_details=ZAR1L%7C0.00%7C0.00%7C0.02%7C0.00%7C31%7C-39%7C-44%7C32;spliceai_max_delta=0.02;gnomad_ac=5753;gnomad_af=0.0378129;gnomad_hom=353;gnomad_het=5047;gnomad_popmax=afr;gnomad_popmax_AF=0.131678;brca_exchange_clinical_significance=Benign_/_Little_Clinical_Significance;task_force_protein_domain=C-terminal_RAD51_binding_domain_(inkl._NLS1_und_BRC-)_;task_force_protein_domain_source=BWRL/ENIGMA;hexplorer=-5.12;hexplorer_mut=-4.84;hexplorer_wt=0.28;hexplorer_rev=4.56;hexplorer_rev_mut=-1.44;hexplorer_rev_wt=-6.00;heredicare_vid=11740058;clinvar=blimblam2;user_classification=3|this_is_a_comment_with\tpecial_characters|2022-10-06_06:00:00|ACMG_standard|-|PS1+very_strong_pathogenic+evidence1+1$PS2+strong_pathogenic+evidence2+1$PP1+very_strong_pathogenic+evidence3+1|;consensus_classification=5|A_random_test_classification|2022-09-07_03:00:00|ACMG_standard|3|PS1+supporting_pathogenic+ev1+1$PS2+strong_pathogenic+ev2+1$PS1+very_strong_pathogenic+ev3+1|;automatic_classification=3|2|2023-11-28_14:41:20|ACMG_SVI_adaptation|PVS1+very_strong+comment_for_criterium+1+general;variation_id=209597;clinvar_summary=reviewed_by_expert_panel:Benign;clinvar_submissions=Benign|2015-01-12|reviewed_by_expert_panel|C2675520:Breast-ovarian_cancer,_familial_2|Evidence-based_Network_for_the_Interpretation_of_Germline_Mutant_Alleles_(ENIGMA)|description:_Class_1_not_pathogenic_based_on_frequency_>1%_in_an_outbred_sampleset._Frequency_0.14_(African),_derived_from_1000_genomes_(2012-04-30).;heredicare_annotation=12345|10|11|15|This_is_a_comment_from_heredicare|2019-08-17;consequences=ENST00000345108|None|None|upstream_gene_variant|modifier|None|None|ZAR1L|None|True|False|False|False|protein_coding|962&ENST00000380152|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|True|True|False|True|protein_coding|10231&ENST00000530893|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|True|False|False|False|protein_coding|9864&ENST00000533490|c.-390%2B372T>C|None|intron_variant|modifier|None|1|ZAR1L|None|True|True|False|True|protein_coding|962&ENST00000544455|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|True|False|False|False|protein_coding|10231&ENST00000614259|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|False|False|False|False|nonsense_mediated_decay|7934&ENST00000680887|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|False|False|False|False|protein_coding|10231&ENSR00000060894|None|None|regulatory_region_variant|modifier|None|None|None|None|False|False|False|False|None|None&ENSM00526233310|None|None|TF_binding_site_variant|modifier|None|None|None|None|False|False|False|False|None|None&ENSM00522614247|None|None|TF_binding_site_variant|modifier|None|None|None|None|False|False|False|False|None|None&NM_000059|None|None|upstream_gene_variant|modifier|None|None|BRCA2|None|True|True|False|True|mRNA|10231&NM_001136571|c.-390%2B372T>C|None|intron_variant|modifier|None|1|ZAR1L|None|True|True|False|True|mRNA|962;assays=2022-08-08|functional|12345.0&2022-08-09|functional|6565.0&2022-08-09|splicing|3654.0;literature=9425226&15342711&16333312&25994375 diff --git a/src/frontend_celery/tests/functional/test_classification_calculation.py b/src/frontend_celery/tests/functional/test_classification_calculation.py index 82ee0dd9..404e363d 100644 --- a/src/frontend_celery/tests/functional/test_classification_calculation.py +++ b/src/frontend_celery/tests/functional/test_classification_calculation.py @@ -16,8 +16,8 @@ -def issue_acmg_endpoint(test_client, scheme_type, classes): - response = test_client.get(url_for("download.calculate_class", scheme_type=scheme_type, selected_classes=classes)) +def issue_acmg_endpoint(test_client, scheme_type, version, classes): + response = test_client.get(url_for("download.calculate_class", scheme_type=scheme_type, version=version, selected_classes=classes)) data = response.get_json() assert response.status_code == 200 return data['final_class'] @@ -30,34 +30,35 @@ def test_acmg_classification_calculation(test_client): """ scheme_type = 'acmg' - - assert issue_acmg_endpoint(test_client, scheme_type, 'pvs1+ps1') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, 'pvs1+pm1+pm4') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, 'pvs1+pm1+pp5') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, 'pvs1+pp1+pp3+pp5') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, 'ps1+ps3+ps4') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, 'ps1+pm1+pm2+pm3') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, 'ps2+pm2+pm4+pp1+pp3') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, 'ps3+pm6+pp1+pp2+pp3+pp4') == 5 - - assert issue_acmg_endpoint(test_client, scheme_type, 'pvs1+pm2') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, 'ps4+pm1') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, 'ps4+pm1+pm2') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, 'ps4+pp1+pp3+pp4') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, 'pm1+pm2+pm4+pm6') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, 'pm1+pm2+pp1+pp2') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, 'pm6+pp1+pp2+pp3+pp4+pp5') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, 'pm1+pp1+pp2+pp4+pp3') == 4 + version = 'v1.0.0' + + assert issue_acmg_endpoint(test_client, scheme_type, version, 'pvs1+ps1') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'pvs1+pm1+pm4') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'pvs1+pm1+pp5') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'pvs1+pp1+pp3+pp5') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'ps1+ps3+ps4') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'ps1+pm1+pm2+pm3') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'ps2+pm2+pm4+pp1+pp3') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'ps3+pm6+pp1+pp2+pp3+pp4') == 5 + + assert issue_acmg_endpoint(test_client, scheme_type, version, 'pvs1+pm2') == 4 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'ps4+pm1') == 4 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'ps4+pm1+pm2') == 4 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'ps4+pp1+pp3+pp4') == 4 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'pm1+pm2+pm4+pm6') == 4 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'pm1+pm2+pp1+pp2') == 4 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'pm6+pp1+pp2+pp3+pp4+pp5') == 4 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'pm1+pp1+pp2+pp4+pp3') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, 'ba1') == 1 - assert issue_acmg_endpoint(test_client, scheme_type, 'bs1+bs3') == 1 - assert issue_acmg_endpoint(test_client, scheme_type, 'bs1+bs2+bp1') == 1 - assert issue_acmg_endpoint(test_client, scheme_type, 'bs1+bs2+bp1+bp2') == 1 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'ba1') == 1 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'bs1+bs3') == 1 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'bs1+bs2+bp1') == 1 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'bs1+bs2+bp1+bp2') == 1 - assert issue_acmg_endpoint(test_client, scheme_type, 'bs1+bp1') == 2 - assert issue_acmg_endpoint(test_client, scheme_type, 'bp1+bp4') == 2 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'bs1+bp1') == 2 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'bp1+bp4') == 2 - assert issue_acmg_endpoint(test_client, scheme_type, 'bp1+bp4+pvs1+pm2') == 3 + assert issue_acmg_endpoint(test_client, scheme_type, version, 'bp1+bp4+pvs1+pm2') == 3 @@ -68,26 +69,27 @@ def test_task_force_classification_calculation(test_client): """ scheme_type = 'task-force' + version = 'v1.0.0' - assert issue_acmg_endpoint(test_client, scheme_type, '1.1') == 1 - assert issue_acmg_endpoint(test_client, scheme_type, '1.1+2.1') == 1 + assert issue_acmg_endpoint(test_client, scheme_type, version, '1.1') == 1 + assert issue_acmg_endpoint(test_client, scheme_type, version, '1.1+2.1') == 1 - assert issue_acmg_endpoint(test_client, scheme_type, '2.1') == 2 - assert issue_acmg_endpoint(test_client, scheme_type, '2.1+5.1') == 2 + assert issue_acmg_endpoint(test_client, scheme_type, version, '2.1') == 2 + assert issue_acmg_endpoint(test_client, scheme_type, version, '2.1+5.1') == 2 - assert issue_acmg_endpoint(test_client, scheme_type, '5.1') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, '5.2+5.6') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, '5.2+5.6+4.3') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, '5.1') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, '5.2+5.6') == 5 + assert issue_acmg_endpoint(test_client, scheme_type, version, '5.2+5.6+4.3') == 5 - assert issue_acmg_endpoint(test_client, scheme_type, '1.2') == 1 - assert issue_acmg_endpoint(test_client, scheme_type, '1.2+1.1') == 1 - assert issue_acmg_endpoint(test_client, scheme_type, '1.2+1.1+2.2') == 1 + assert issue_acmg_endpoint(test_client, scheme_type, version, '1.2') == 1 + assert issue_acmg_endpoint(test_client, scheme_type, version, '1.2+1.1') == 1 + assert issue_acmg_endpoint(test_client, scheme_type, version, '1.2+1.1+2.2') == 1 - assert issue_acmg_endpoint(test_client, scheme_type, '2.5') == 2 - assert issue_acmg_endpoint(test_client, scheme_type, '2.5+2.2') == 2 + assert issue_acmg_endpoint(test_client, scheme_type, version, '2.5') == 2 + assert issue_acmg_endpoint(test_client, scheme_type, version, '2.5+2.2') == 2 - assert issue_acmg_endpoint(test_client, scheme_type, '4.1') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, '4.2+3.3') == 4 + assert issue_acmg_endpoint(test_client, scheme_type, version, '4.1') == 4 + assert issue_acmg_endpoint(test_client, scheme_type, version, '4.2+3.3') == 4 - assert issue_acmg_endpoint(test_client, scheme_type, '3.4') == 3 \ No newline at end of file + assert issue_acmg_endpoint(test_client, scheme_type, version, '3.4') == 3 \ No newline at end of file diff --git a/src/frontend_celery/tests/functional/test_variant_io.py b/src/frontend_celery/tests/functional/test_variant_io.py index 14db753e..2b836c13 100644 --- a/src/frontend_celery/tests/functional/test_variant_io.py +++ b/src/frontend_celery/tests/functional/test_variant_io.py @@ -99,6 +99,9 @@ def test_export_variant_to_vcf(test_client): with open(test_data_dir + '/variant_52.vcf', 'r') as f1: vcf_variant_52 = f1.read() + + with open(test_data_dir + "/variant_52_actual.vcf", "w") as f1: + f1.write(data) utils.compare_vcf(vcf_variant_52, data) utils.compare_vcf(data, vcf_variant_52) diff --git a/src/frontend_celery/tests/functional/test_variant_routes.py b/src/frontend_celery/tests/functional/test_variant_routes.py index 32263b20..3b9b072d 100644 --- a/src/frontend_celery/tests/functional/test_variant_routes.py +++ b/src/frontend_celery/tests/functional/test_variant_routes.py @@ -11,6 +11,7 @@ from io import StringIO, BytesIO import common.functions as functions import time +import utils basepath = os.path.dirname(os.path.dirname(os.path.abspath(__file__))) test_data_dir = basepath + "/data" @@ -79,8 +80,6 @@ def test_browse(test_client): response = test_client.get(url_for("variant.search", page_size = 5, sort_by = 'gnomic_position'), follow_redirects=True) data = html.unescape(response.data.decode('utf8')) - with open("/mnt/storage2/users/ahdoebm1/HerediVar/src/frontend_celery/tests/test_dat/browse_01.html", "w") as file: - file.write(data) assert response.status_code == 200 assert data.count('name="variant_row"') == 5 variant_ids = [139, 130, 15, 146, 52] @@ -456,19 +455,16 @@ def test_variant_history(test_client): data = html.unescape(response.data.decode('utf8')) assert response.status_code == 200 - print(data) - conn = Connection(['super_user']) - consensus_classifications = conn.get_consensus_classifications_extended(variant_id, most_recent=False) - user_classifications = conn.get_user_classifications_extended(variant_id) + variant = conn.get_variant(variant_id) conn.close() # this could be improved by making custom html attributes saving the type & id of the classification - if consensus_classifications is not None: - assert data.count('consensus classification') == len(consensus_classifications) + 2 # add two because this string is also in the caption and the legend + assert variant.consensus_classifications is not None + assert data.count('consensus classification') == len(variant.consensus_classifications) + 2 # add two because this string is also in the caption and the legend - if user_classifications is not None: - assert data.count('user classification') == len(user_classifications) + 1 # also contained in the legend + assert variant.user_classifications is not None + assert data.count('user classification') == len(variant.user_classifications) + 1 # also contained in the legend @@ -596,7 +592,27 @@ def test_classify(test_client): data = html.unescape(response.data.decode('utf8')) assert response.status_code == 200 assert "Successfully updated user classification" not in data - assert "There are criteria which can not be activated with the provided scheme (TP_53)" not in data + assert "There are criteria which can not be activated with the provided scheme" not in data + + time.sleep(2) # this is nececssary to not have multiple classifications at the same time + + + ##### test posting criteria to a deactivated scheme ##### + response = test_client.post( + url_for("variant.classify", variant_id=variant_id), + data = { + 'final_class': "2", + 'comment': "This is a test comment update 2.", + 'pm3': "Evidence for pm3 given in this field", # forbidden for amg tp53 + 'pm3_strength': "pm", + 'pm3_state': "selected", + 'scheme': "4" + }, + follow_redirects=True + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + utils.assert_flash_message("Unknown or deprecated classification scheme provided. Please provide a different one.", data) time.sleep(2) # this is nececssary to not have multiple classifications at the same time @@ -670,6 +686,68 @@ def test_classify(test_client): conn.close() + + +def test_delete_user_classification(test_client): + """ + This tests if user classifications can be deleted by the user who created it and not by any other user + """ + + user_id = 3 + + ##### wrong variant id ##### + variant_id = 169 + user_classification_id = 30 + + response = test_client.get(url_for("variant.delete_classification", variant_id=variant_id, user_classification_id=user_classification_id), follow_redirects=True) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 404 + + ##### successful deletion ##### + variant_id = 168 + user_classification_id = 30 + + response = test_client.get(url_for("variant.delete_classification", variant_id=variant_id, user_classification_id=user_classification_id), follow_redirects=True) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert data == "success" + + + + conn = Connection(['super_user']) + variant = conn.get_variant(variant_id) + conn.close() + + assert variant is not None + user_classification = None + for cl in variant.user_classifications: + if str(cl.id) == str(user_classification_id): + user_classification = cl + assert user_classification is None + + + ##### not allowed to delete ##### + variant_id = 168 + user_classification_id = 31 + + response = test_client.get(url_for("variant.delete_classification", variant_id=variant_id, user_classification_id=user_classification_id), follow_redirects=True) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 405 + + conn = Connection(['super_user']) + variant = conn.get_variant(variant_id) + conn.close() + + assert variant is not None + user_classification = None + for cl in variant.user_classifications: + if str(cl.id) == str(user_classification_id): + user_classification = cl + assert user_classification is not None + + + + def test_create_variant(test_client): @@ -832,3 +910,404 @@ def test_create_variant_from_hgvs(test_client): assert "214767531" in data + +def test_hide_scheme(test_client): + """ + This tests if the user can hide/disable a scheme + """ + + user_id = 3 + + ##### successful hide ##### + scheme_id = 2 + is_active = 'false' + + # do a nonsense get request first, because pytest is trash + response = test_client.get(url_for("variant.create"), follow_redirects=True) + assert response.status_code == 200 + + + response = test_client.post( + url_for("variant.hide_scheme"), + data={ + "scheme_id": scheme_id, + "is_active": is_active + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert data == "success" + + conn = Connection() + scheme = conn.get_classification_scheme(scheme_id) + assert scheme[5] == 0 + conn.close() + + ##### successful unhide ##### + is_active = 'true' + + response = test_client.post( + url_for("variant.hide_scheme"), + data={ + "scheme_id": scheme_id, + "is_active": is_active + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert data == "success" + + conn = Connection() + scheme = conn.get_classification_scheme(scheme_id) + assert scheme[5] == 1 + conn.close() + + + + + +def test_check_variant(test_client): + """ + Test the check variant endpoint + """ + + ##### check availability ##### + response = test_client.get(url_for("variant.check"), follow_redirects=True) + assert response.status_code == 200 + + + ##### check successful snv ##### + #chr2 214767531 C T -- grch38 + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "214767531", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: success" in data + assert "Message: hg38_msg=HG38 variant would be: chr2-214767531-C-T" in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "214.767.531", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: success" in data + assert 'Message: hg38_msg=HG38 variant would be: chr2-214767531-C-T' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "2", + "pos": "214767531", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: success" in data + assert 'Message: hg38_msg=HG38 variant would be: chr2-214767531-C-T' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "CHR2", + "pos": "214767531", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: success" in data + assert 'Message: hg38_msg=HG38 variant would be: chr2-214767531-C-T' in data + + ##### missing data ##### + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert "Message: hg38_msg=Position is invalid: None" in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "214767531", + "ref": "", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Invalid reference sequence! The sequence must contain only ACGT and must have 0 < length < 1000: ""' in data + + + ##### invalid position ##### + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "-1", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Position is invalid: -1' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "0", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=VcfCheck runtime ERROR:' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "xya1234", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Position is invalid: xya1234' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": " ", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Position is invalid: None' in data + + ##### invalid chromosome ##### + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chrL", + "pos": "214767531", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Chromosome is invalid: chrL' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "", + "pos": "214767531", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Chromosome is invalid:' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": " ", + "pos": "214767531", + "ref": "C", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Chromosome is invalid:' in data + + ##### invalid sequence ##### + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "214767531", + "ref": "N", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Invalid reference sequence! The sequence must contain only ACGT and must have 0 < length < 1000: "N"' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "214767531", + "ref": "ÖP", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Invalid reference sequence! The sequence must contain only ACGT and must have 0 < length < 1000: "ÖP"' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "214767531", + "ref": "C", + "alt": "N", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Invalid alternative sequence! The sequence must contain only ACGT and must have 0 < length < 1000: "N"' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "214767531", + "ref": "C", + "alt": " ", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Invalid alternative sequence! The sequence must contain only ACGT and must have 0 < length < 1000: ""' in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "214767531", + "ref": "A", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + #with open("/mnt/storage2/users/ahdoebm1/HerediVar/test.txt", "w") as f: + # f.write(data) + assert "Message: hg38_msg= ERROR: Reference base(s) not correct. Is 'A', should be 'C'!" in data + + response = test_client.post( + url_for("variant.check"), + data={ + "chrom": "chr2", + "pos": "214767531", + "ref": "T", + "alt": "T", + "genome": "GRCh38" + }, + follow_redirects=True, + content_type='multipart/form-data' + ) + data = html.unescape(response.data.decode('utf8')) + assert response.status_code == 200 + assert "Status: error" in data + assert 'Message: hg38_msg=Equal reference and alternative base are not allowed.' in data diff --git a/src/frontend_celery/webapp/templates/variant/check.html b/src/frontend_celery/webapp/templates/variant/check.html index fe456888..8ae57d1c 100644 --- a/src/frontend_celery/webapp/templates/variant/check.html +++ b/src/frontend_celery/webapp/templates/variant/check.html @@ -37,6 +37,7 @@

Check results

{% for chr in chroms %} {% endfor %} +
Please provide a chromosome! diff --git a/src/frontend_celery/webapp/variant/variant_routes.py b/src/frontend_celery/webapp/variant/variant_routes.py index f040aa1e..66db1a4c 100644 --- a/src/frontend_celery/webapp/variant/variant_routes.py +++ b/src/frontend_celery/webapp/variant/variant_routes.py @@ -339,9 +339,14 @@ def classify(variant_id): classification_is_valid = str(classification) in allowed_classes scheme_class = '-' + scheme_id_is_valid = True if not without_scheme: - scheme_class = get_scheme_class(criteria, classification_schemas[scheme_id]['scheme_type']) - scheme_class = scheme_class.json['final_class'] + if scheme_id in classification_schemas: + scheme_class = get_scheme_class(criteria, classification_schemas[scheme_id]['scheme_type']) + scheme_class = scheme_class.json['final_class'] + else: + flash("Unknown or deprecated classification scheme provided. Please provide a different one.", "alert-danger") + scheme_id_is_valid = False # flash error messages if (not scheme_classification_is_valid) and (not without_scheme): # error in scheme @@ -352,7 +357,7 @@ def classify(variant_id): flash(literature_message, "alert-danger") # actually submit the data to the database - if classification_is_valid and scheme_classification_is_valid and literature_is_valid: + if classification_is_valid and scheme_classification_is_valid and literature_is_valid and scheme_id_is_valid: # always handle the user classification & literature user_classification_id, classification_received_update, is_new_classification = handle_user_classification(variant, user_id, classification, comment, scheme_id, scheme_class, conn) previous_selected_literature = [] # a new classification -> no previous sleected literature @@ -405,7 +410,7 @@ def delete_classification(): user_classification = None for cl in variant.user_classifications: - if str(cl.id) == user_classification_id: + if str(cl.id) == str(user_classification_id): user_classification = cl if user_classification is None: @@ -469,8 +474,13 @@ def consensus_classify(variant_id): scheme_classification_is_valid, scheme_message = is_valid_scheme(criteria, classification_schemas[scheme_id]) classification_is_valid = str(classification) in allowed_classes - scheme_class = get_scheme_class(criteria, classification_schemas[scheme_id]['scheme_type']) # always calculate scheme class because no scheme is not allowed here! - scheme_class = scheme_class.json['final_class'] + scheme_id_is_valid = True + if scheme_id in classification_schemas: + scheme_class = get_scheme_class(criteria, classification_schemas[scheme_id]['scheme_type']) # always calculate scheme class because no scheme is not allowed here! + scheme_class = scheme_class.json['final_class'] + else: + flash("Unknown or deprecated classification scheme provided. Please provide a different one.", "alert-danger") + scheme_id_is_valid = False # actually submit the data to the database if not scheme_classification_is_valid: # error in scheme @@ -480,7 +490,7 @@ def consensus_classify(variant_id): if not literature_is_valid: flash(literature_message, "alert-danger") - if classification_is_valid and scheme_classification_is_valid and literature_is_valid: + if classification_is_valid and scheme_classification_is_valid and literature_is_valid and scheme_id_is_valid: # insert consensus classification classification_id = handle_consensus_classification(variant, classification, comment, scheme_id, pmids, text_passages, criteria, classification_schemas[scheme_id]['description'], scheme_class, conn)