Starting

Initialising…

BRCA1

Final classification

Likely Pathogenic

BRCA1 c.131G>A · p.Cys44Tyr

BRCA1

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.

Gene

BRCA1

Transcript

NM_007294.4

HGVS · transcript:coding

NM_007294.4:c.131G>A

Consequence

N/A

GRCh38

chr17:43115729 C>T

GRCh37

chr17:41267746 C>T

Basis Official ENIGMA BRCA1/BRCA2 VCEP final-classification framework (Specifications v1.2 Table 4 combination rules) applied to the adjudicated criteria. ▾

Official ENIGMA BRCA1/BRCA2 VCEP final-classification framework (Specifications v1.2 Table 4 combination rules) applied to the adjudicated criteria.

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 ↗

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

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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

→PP3 supports · met →PS3 supports · met

PMID 32546644

PMID 32546644 ↗

Found

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

Applied to

→PP3 supports · met →PS3 supports · met

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots