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 ↗

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_007294.3 · variants mapped to exon structure

BRCA1 NM_007294.3

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 15 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 · 4

Strength Supporting Moderate Strong Very strong

PS3 strong Pathogenic

In a calibrated functional study, this variant showed loss of function/complete functional impact relative to wild type, and ENIGMA BRCA1 Table 9 assigns PS3 at strong strength for c.5140G>T (p.Val1714Phe). This supports a damaging effect on BRCA1 protein function.

ENIGMA Table 9 row: PS3 Strong for c.5140G>TSupplementary Table 4: Functional impact - complete / LOFFindlay saturation genome editing data

PMID:30209399 ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the ENIGMA BRCA1 specification, absence from controls supports PM2 at supporting strength.

Absent from gnomAD v2.1Absent from gnomAD v4.1

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 supporting Pathogenic

This missense variant lies within the BRCA1 BRCT repeats, a clinically important functional domain (aa 1650-1857). BayesDel no-AF is 0.482282, which is above the ENIGMA PP3 threshold of 0.28 for damaging protein effect, REVEL is 0.812, and SpliceAI is low at 0.09; together these data support a damaging protein effect rather than a splice-mediated explanation.

BRCT domain locationBayesDel no-AF 0.482282REVEL 0.812

cspec ↗spliceai ↗

PP5 supporting Pathogenic

Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.

ENIGMA BRCA1 specification marks PP5 not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 7 not met · 8 not assessed

Pathogenic

PVS1 This variant is a missense substitution and does not fall into the BRCA1 null-variant categories used for PVS1.

PS1 No qualifying previously classified pathogenic or likely pathogenic reference variant with the same amino acid change or the same predicted splicing effect was identified in the reviewed sources, so PS1 was not applied.

PS4 No case-control study or exact affected-versus-control enrichment data demonstrating significant overrepresentation of this variant were identified, so PS4 was not applied.

PM3 No evidence was identified that this variant was observed with a second BRCA1 pathogenic variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not applied.

PP1 No quantitative co-segregation data for this variant were identified, so PP1 was not applied.

PP4 No variant-level clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant in the reviewed BRCA1 clinical-history resource, so PP4 was not applied.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the ENIGMA BA1 stand-alone threshold of filter allele frequency greater than 0.1%.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the ENIGMA BS1 population thresholds of filter allele frequency greater than 0.002% or greater than 0.01%.

BS2 No point-based evidence from individuals lacking features of BRCA1-related Fanconi anemia was identified, so BS2 was not applied.

BS3 Available functional evidence does not show no damaging effect.

BS4 No quantitative lack-of-segregation evidence for this variant was identified, so BS4 was not applied.

BP1 BP1_Strong applies to missense variants outside the BRCA1 clinically important domains with no predicted splice effect.

BP4 For a BRCA1 missense variant in a clinically important domain, BP4 requires BayesDel no-AF 0.15 or lower and SpliceAI 0.1 or lower.

BP5 No variant-level clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this variant in the reviewed BRCA1 clinical-history resource, so BP5 was not applied.

BP7 BP7 in this framework requires qualifying RNA evidence and/or variant-type conditions that are not met here.

N/A · 9 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · 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 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

1papers cited

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

Accurate classification of BRCA1 variants with saturation genome editing.

PMID 30209399 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 strong

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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