Starting

Initialising…

BRCA1

Final classification

Likely Pathogenic

BRCA1 c.5140G>T · p.Val1714Phe

BRCA1

Gene

BRCA1

Transcript

NM_007294.3

HGVS · transcript:coding

NM_007294.3:c.5140G>T

Consequence

N/A

GRCh38

chr17:43063886 C>A

GRCh37

chr17:41215903 C>A

Basis ClinGen ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules (CSPEC/VCEP override). ▾

ClinGen ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules (CSPEC/VCEP override).

Classification rationale

PS3PM2PP3PP5 Likely Pathogenic

BRCA1 c.5140G>T

The BRCA1 c.5140G>T (p.Val1714Phe) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the overall classification is Likely Pathogenic with expert panel review.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.² In a calibrated BRCA1 functional study, this variant showed complete functional impact consistent with loss of function, and ENIGMA assigns PS3_Strong for this variant.³ Computational data support a damaging protein effect because the variant is in the BRCT repeats, BayesDel no-AF is 0.482282, and REVEL is 0.812, while SpliceAI predicts no significant splice effect with a max delta score of 0.09.⁴

PS3 + PM2 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 PMID:30209399 ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18

4 bayesdelrevelspliceai ↗vcep_appendices_v1_2_2024_11_18cspec ↗

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 (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely 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 = 0.09). REVEL score = 0.812. BayesDel score = 0.482282.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

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 PMID:30209399

PMID PMID:30209399 ↗

Found