owencqueen/cgbench_data huggingface dataset:
Gene: BRCA1 (HGNC:1100)
Evidence Code: PVS1 — Original ACMG Summary
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.
Caveats:
 • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
 • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
 • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
 • Use caution in the presence of multiple transcripts.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PVS1 — Very Strong
Modification Type: Gene-specific
Null 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.


Well-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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PVS1 — Strong
Modification Type: Gene-specific
Null 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.


Well-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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PVS1 — Moderate
Modification Type: Gene-specific
Null 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.


Well-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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PVS1 — Supporting
Modification Type: Gene-specific
Null 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.


Well-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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PS1 — Original ACMG Summary
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Example: Val->Leu caused by either G>C or G>T in the same codon.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PS1 — Strong
Modification Type: General recommendation
Apply 
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)).


Apply 
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. 


See Specifications Table 5 and Appendix E, J and K for details.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PS1 — Moderate
Modification Type: General recommendation
Apply 
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)).


Apply 
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.


See Specifications Table 5 and Appendix E, J and K for details.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PS1 — Supporting
Modification Type: General recommendation
Apply 
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.


See Specifications Table 5 and Appendix E, J and K for details.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PS2 — Original ACMG Summary
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Note: 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PS3 — Strong
Modification Type: General recommendation
Well-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.


Well-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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PS4 — Original ACMG Summary
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
Note 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.
Note 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PS4 — Strong
Modification Type: Clarification,Gene-specific
The 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM1 — Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM2 — Original ACMG Summary
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Caveat: Population data for indels may be poorly called by next generation sequencing.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM2 — Supporting
Modification Type: Gene-specific
Absent 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM3 — Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM3 — Strong
Modification Type: Gene-specific
Apply 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:


(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
.


(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.


See 
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.


PM3_Strong = ≥4 points
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM3 — Moderate
Modification Type: Gene-specific
Apply 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:


(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
.


(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.


See 
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.


PM3 = 2 points
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM3 — Supporting
Modification Type: Gene-specific
Apply 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:


(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
.


(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.


See 
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.


PM3_Supporting = 1 point
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM5 — Original ACMG Summary
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Example: Arg156His is pathogenic; now you observe Arg156Cys.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM5 — Strong
Modification Type: Other
Protein 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM5 — Moderate
Modification Type: Other
Protein 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM5 — Supporting
Modification Type: Other
Protein 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP1 — Original ACMG Summary
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Note: May be used as stronger evidence with increasing segregation data.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP1 — Strong
Modification Type: Gene-specific
Co-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.


Apply weight as per Bayes Score:


PP1_Strong – LR>18.7:1


PP1_Very Strong – LR>350:1
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP1 — Moderate
Modification Type: Gene-specific
Co-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.


Apply weight as per Bayes Score:


PP1_Moderate – LR>4.3:1
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP1 — Supporting
Modification Type: Gene-specific
Co-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.


Apply weight as per Bayes Score:


PP1 - LR >2.08:1
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP2 — Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP3 — Original ACMG Summary
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP3 — Supporting
Modification Type: Gene-specific
Apply 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.


Apply 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.


See Specifications Figure1A and Appendix J for details.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP4 — Strong
Modification Type: Gene-specific
Breast 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.


PP4_Strong – LR>18.7:1


PP4_Very Strong – LR>350:1


Combined LR 1.00-2.08 is not informative (PP4 not applicable).


See Specifications Table7 and Appendix B for details.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP4 — Moderate
Modification Type: Gene-specific
Breast 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.


PP4_Moderate – LR>4.3:1


Combined LR 1.00-2.08 is not informative (PP4 not applicable).


See Specifications Table7 and Appendix B for details.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP4 — Supporting
Modification Type: Gene-specific
Breast 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.


PP4 - LR >2.08:1 


Combined LR 1.00-2.08 is not informative (PP4 not applicable).


See Specifications Table7 and Appendix B for details.
Gene: BRCA1 (HGNC:1100)
Evidence Code: PP5 — Original ACMG Summary
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BA1 — Stand Alone
Modification Type: Gene-specific
Filter 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS1 — Strong
Modification Type: Gene-specific
Filter 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS1 — Supporting
Modification Type: Gene-specific
Filter 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS2 — Original ACMG Summary
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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS2 — Strong
Modification Type: Gene-specific
Applied 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.


BS2 = ≥ 4 points
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS2 — Moderate
Modification Type: Gene-specific
Applied 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.


BS2_Moderate = 2 points
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS2 — Supporting
Modification Type: Gene-specific
Applied 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.


BS2_Supporting = 1 points
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS3 — Strong
Modification Type: Gene-specific
Well-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.


Well-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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS4 — Original ACMG Summary
Lack of segregation in affected members of a family.
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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS4 — Strong
Modification Type: Gene-specific
Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.


Apply weight as per Bayes Score:


BS4 - LR <0.05:1


BS4_VeryStrong – LR <0.00285:1
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS4 — Moderate
Modification Type: Gene-specific
Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.


Apply weight as per Bayes Score:


BS4_Moderate - LR <0.23:1
Gene: BRCA1 (HGNC:1100)
Evidence Code: BS4 — Supporting
Modification Type: Gene-specific
Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.


Apply weight as per Bayes Score:


BS4_Supporting  - LR 0.23-0.48:1
Gene: BRCA1 (HGNC:1100)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BP1 — Strong
Modification Type: Gene-specific,Strength
Apply 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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BP2 — Original ACMG Summary
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.
Gene: BRCA1 (HGNC:1100)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.