BRCA1

Final classification

Likely Pathogenic

BRCA1 c.5089T>C · p.Cys1697Arg

BRCA1

The BRCA1 c.5089T>C (p.Cys1697Arg) variant has not been observed in COSMIC and has been reported in ClinVar, including a pathogenic expert-panel classification from ClinGen ENIGMA.

Gene

BRCA1

Transcript

NM_007294.3

HGVS · transcript:coding

NM_007294.3:c.5089T>C

Consequence

N/A

GRCh38

chr17:43063937 A>G

GRCh37

chr17:41215954 A>G

Basis ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP override in final_classification_framework). ▾

ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP override in final_classification_framework).

Classification rationale

PS3PM2PP3PP5 Likely Pathogenic

BRCA1 c.5089T>C

The BRCA1 c.5089T>C (p.Cys1697Arg) variant has not been observed in COSMIC and has been reported in ClinVar, including a pathogenic expert-panel classification from ClinGen ENIGMA.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.² In calibrated functional studies summarized by the BRCA1 expert-panel resources, this variant showed loss of BRCA1 function, and the expert-panel table assigns PS3_Strong.³ Computational evidence supports a damaging protein effect because the variant is in the BRCA1 BRCT repeats, BayesDel is 0.398132 (above the PP3 threshold of 0.28), and REVEL is 0.914, while SpliceAI predicts no significant splice effect with a max delta score of 0.08.⁴

PS3 + PM2 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001

4 cspec ↗vcep_appendices_v1_2_2024_11_18bayesdelrevelspliceai ↗

Gene diagram · NM_007294.3 · variants mapped to exon structure

BRCA1 NM_007294.3

Fetching transcript structure from UCSC…

Applied criteria · 4 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 Likely pathogenic (6 clinical laboratories) and as Pathogenic (5 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.914. BayesDel score = 0.398132.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

5papers cited

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

PMID vcep_appendices_v1_2_2024_11_18

PMID vcep_appendices_v1_2_2024_11_18 ↗

Found