Classification rationale

PS3PM2PP3 Likely Pathogenic

BRCA1 c.131G>A

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.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.² 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.³ 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).⁴

PS3 + PM2 + PP3 → Likely Pathogenic

1 cosmicclinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 Specifications_Table9_V1.2_2024-11-18.xlsx3020939932546644

4 SupplementaryTables_V1.2_2024-11-18.xlsxspliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_007294.4 · variants mapped to exon structure

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PS3 Strong review Pathogenic

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.

Table 9 row: BRCA1 c.131G>A p.(Cys44Tyr) -> PS3 Strong.Table 9 cites Findlay 2018 (PMID:30209399) and Bouwman 2020 (PMID:32546644).Supplementary Table 4 lists c.131G>A as Functional impact - complete / LOF.

cspec ↗

PM2 Supporting review Pathogenic

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.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.ENIGMA BRCA1 uses PM2 at Supporting strength for absence from controls.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 Supporting review Pathogenic

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.

ENIGMA BRCA1 PP3 applies to missense variants inside a clinically important functional domain with BayesDel no-AF ≥0.28.Supplementary Table ST13 lists BRCA1 c.131G>A p.Cys44Tyr in the RING domain with BayesDel 0.57077.SpliceAI max delta score is 0.01.

cspec ↗spliceai ↗

Assessed · not applied · 6 not met · 8 not assessed

Pathogenic

PS1 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.

PS4 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.

PM3 No evidence was identified for biallelic BRCA1 findings in a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 cannot be applied.

PP1 No quantitative segregation data were identified to support PP1.

PP4 No multifactorial clinical likelihood ratio meeting ENIGMA BRCA1 PP4 thresholds was identified for this variant.

Benign

BA1 The variant is absent from the reviewed gnomAD datasets and does not meet the high population frequency threshold required for BA1.

BS1 The variant is absent from the reviewed gnomAD datasets and does not meet the population frequency threshold required for BS1.

BS2 No qualifying observations in individuals without features of recessive BRCA1-related disease were identified to score BS2.

BS3 Curated ENIGMA functional evidence supports a damaging effect rather than a neutral effect; Table 9 assigns PS3_Strong, so BS3 is not met.

BS4 No quantitative lack-of-segregation evidence was identified to support BS4.

BP1 BP1_Strong is restricted to silent, missense, or in-frame variants outside a clinically important functional domain with no splicing effect.

BP4 Although SpliceAI predicts no significant splice impact, BP4 for missense variants inside a clinically important functional domain also requires BayesDel no-AF ≤0.15.

BP5 No multifactorial clinical likelihood ratio against pathogenicity was identified to support BP5 at any strength.

BP7 BP7 in the ENIGMA BRCA1 framework is intended for silent or intronic variants, or for RNA-only evidence showing no damaging effect.

N/A · 11 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Oncogenic

OncoKB classifies this variant as Oncogenic; biological effect: Loss-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107367559, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

PMID 30209399

PMID 30209399 ↗

Found

Table 9 cites Findlay 2018 (PMID:30209399) and Bouwman 2020 (PMID:32546644).

Applied to

→PS3 Strong

→PP3 Supporting

PMID 32546644

PMID 32546644 ↗

Found

Table 9 cites Findlay 2018 (PMID:30209399) and Bouwman 2020 (PMID:32546644).

Applied to

→PS3 Strong

→PP3 Supporting

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots

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