LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-16
Case ID: NM_007294.4_c.131G_A_20260416_033842
Framework: ACMG/AMP 2015
Variant classification summary

NM_007294.4:c.131G>A

BRCA1  · NP_009225.1:p.(Cys44Tyr)  · NM_007294.4
GRCh37: chr17:41267746 C>T  ·  GRCh38: chr17:43115729 C>T
Gene: BRCA1 Transcript: NM_007294.4
Final call
Likely Pathogenic
PS3 PM2_Supporting PP3
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Cys44Tyr)
gnomAD AF
ClinVar
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The BRCA1 c.131G>A (p.Cys44Tyr) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including ENIGMA expert panel review.
2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
3
Calibrated functional studies have shown a damaging loss-of-function effect for p.Cys44Tyr, and ENIGMA BRCA1 Table 9 assigns PS3_Strong based on these data.
4
The missense change affects the BRCA1 RING domain, a clinically important functional domain, with BayesDel 0.57077 supporting deleterious impact, while SpliceAI predicts no meaningful splice effect (max delta 0.01).
Final determination: Likely Pathogenic based on 1 strong pathogenic criterion and 2 supporting pathogenic criteria (PS3 + PM2_Supporting + PP3).
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A NM_007294.4:c.131G>A is a missense variant, and the reviewed evidence does not show a null effect or an RNA assay result that would justify PVS1 under the ENIGMA BRCA1 specification.
cspec spliceai
PS1 Not assessed No reviewed source established a separately classified pathogenic missense variant causing the same amino acid substitution or an equivalent proven splicing effect for PS1 application.
cspec clinvar
PS2 N/A PS2 is listed as not applicable in the ENIGMA BRCA1 specification.
cspec
PS3 Met ENIGMA BRCA1 Table 9 assigns PS3_Strong to c.131G>A (p.Cys44Tyr), reporting two calibrated studies showing protein function similar to pathogenic control variants. Supplementary functional data also show complete functional impact/loss of function.
cspec Specifications_Table9_V1.2_2024-11-18.xlsx SupplementaryTables_V1.2_2024-11-18.xlsx
PS4 Not assessed The reviewed materials show database observations, including ClinVar submissions and one COSMIC somatic observation, but no qualifying case-control analysis with a significant enrichment over controls as required for PS4.
cspec clinvar cosmic
PM1 N/A PM1 is listed as not applicable in the ENIGMA BRCA1 specification.
cspec
PM2 Met The variant is absent from gnomAD v2.1 and gnomAD v4.1 in the reviewed population datasets, supporting rarity consistent with PM2_Supporting under the BRCA1 ENIGMA framework.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed No evidence was identified for biallelic BRCA1 findings in a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 cannot be applied.
cspec clinvar
PM4 N/A PM4 is listed as not applicable in the ENIGMA BRCA1 specification.
cspec
PM5 N/A Under the ENIGMA BRCA1 specification, PM5 is defined for protein-truncating variants in eligible exons and does not apply to this missense variant.
cspec Specifications_Table4_V1.2_2024-11-18.xlsx
PM6 N/A PM6 is listed as not applicable in the ENIGMA BRCA1 specification.
cspec
PP1 Not assessed No quantitative segregation data were identified to support PP1.
cspec literature_pass
PP2 N/A PP2 is listed as not applicable in the ENIGMA BRCA1 specification.
cspec
PP3 Met This missense variant lies in the BRCA1 RING domain (aa 2-101), a clinically important functional domain in the ENIGMA BRCA1 framework, and the reviewed bioinformatic dataset shows a BayesDel score of 0.57077, above the PP3 threshold. SpliceAI predicts no meaningful splice impact, supporting a protein-based deleterious interpretation.
cspec SupplementaryTables_V1.2_2024-11-18.xlsx spliceai
PP4 Not assessed No multifactorial clinical likelihood ratio meeting ENIGMA BRCA1 PP4 thresholds was identified for this variant.
cspec HUMU-40-1557-s001.xlsx
PP5 N/A PP5 is listed as not applicable in the ENIGMA BRCA1 specification.
cspec
BA1 Not met The variant is absent from the reviewed gnomAD datasets and does not meet the high population frequency threshold required for BA1.
cspec gnomad_v2 gnomad_v4
BS1 Not met The variant is absent from the reviewed gnomAD datasets and does not meet the population frequency threshold required for BS1.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed No qualifying observations in individuals without features of recessive BRCA1-related disease were identified to score BS2.
cspec clinvar
BS3 Not met Curated ENIGMA functional evidence supports a damaging effect rather than a neutral effect; Table 9 assigns PS3_Strong, so BS3 is not met.
Specifications_Table9_V1.2_2024-11-18.xlsx SupplementaryTables_V1.2_2024-11-18.xlsx
BS4 Not assessed No quantitative lack-of-segregation evidence was identified to support BS4.
cspec literature_pass
BP1 Not met BP1_Strong is restricted to silent, missense, or in-frame variants outside a clinically important functional domain with no splicing effect. This variant is within the BRCA1 RING domain and has damaging functional evidence.
cspec SupplementaryTables_V1.2_2024-11-18.xlsx spliceai
BP2 N/A BP2 is listed as not applicable in the ENIGMA BRCA1 specification.
cspec
BP3 N/A BP3 is listed as not applicable in the ENIGMA BRCA1 specification.
cspec
BP4 Not met Although SpliceAI predicts no significant splice impact, BP4 for missense variants inside a clinically important functional domain also requires BayesDel no-AF ≤0.15. The reviewed bioinformatic dataset shows BayesDel 0.57077, so BP4 is not met.
cspec SupplementaryTables_V1.2_2024-11-18.xlsx spliceai
BP5 Not assessed No multifactorial clinical likelihood ratio against pathogenicity was identified to support BP5 at any strength.
cspec HUMU-40-1557-s001.xlsx
BP6 N/A BP6 is listed as not applicable in the ENIGMA BRCA1 specification.
cspec
BP7 Not met BP7 in the ENIGMA BRCA1 framework is intended for silent or intronic variants, or for RNA-only evidence showing no damaging effect. This is a missense variant within a clinically important domain, and benign RNA-only or neutral functional evidence was not identified.
cspec spliceai Specifications_Table9_V1.2_2024-11-18.xlsx
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