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 ↗

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 calibrated functional studies summarized by the BRCA1 expert-panel specification, this variant showed abnormal protein function consistent with loss of function. Table 9 assigns PS3_Strong for c.5089T>C, and the supplementary functional dataset records complete functional impact/LOF.

Specifications Table 9 row for BRCA1 c.5089T>C assigns PS3 Strong.Supplementary Table 4 records Functional impact - complete and LOF for c.5089T>C.Parsons supplementary dataset shows posterior probability 0.9998665902833963 and Pathogenic classification with functional impact - complete.

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. That absence supports rarity in population controls and is consistent with PM2_Supporting.

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

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP3 supporting Pathogenic

This missense variant lies within the BRCA1 BRCT repeats, a clinically important functional domain, and computational evidence supports a damaging protein effect. BayesDel is 0.398132, which is above the BRCA1 PP3 threshold of 0.28, REVEL is 0.914, and SpliceAI does not predict a meaningful splice effect (max delta score 0.08). These findings support PP3.

Residue 1697 is within the BRCA1 BRCT domain.BayesDel score 0.398132.REVEL score 0.914.

cspec ↗spliceai ↗

PP5 supporting Pathogenic

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

CSPEC lists PP5 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 9 not met · 6 not assessed

Pathogenic

PVS1 This missense variant results in p.(Cys1697Arg) and is not a nonsense, frameshift, initiation-loss, or canonical +/-1,2 splice variant.

PS1 No evidence was identified that this variant produces the same pathogenic amino acid or the same pathogenic splicing consequence as a previously established BRCA1 pathogenic variant.

PS4 Although this variant has been reported in affected individuals and is classified as pathogenic by the ClinVar ENIGMA expert panel, no case-control comparison with a significant odds ratio or lower confidence interval excluding 2.0 was identified.

PM3 No evidence was identified for biallelic BRCA1 disease with a second variant in trans in a patient with a phenotype consistent with BRCA1-related Fanconi anemia.

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

PP4 In the BRCA1 clinical-history likelihood-ratio table, this variant has an LR of 1.211619929099039 based on 1 proband.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the BA1 population threshold.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the BS1 thresholds.

BS2 No scored observations of this variant in individuals without features of BRCA1-related Fanconi anemia were identified under the BRCA1 expert-panel BS2 framework.

BS3 Available functional evidence does not show normal BRCA1 function.

BS4 No quantitative non-segregation data were identified for this variant, so BS4 was not applied.

BP1 This missense variant is located within the BRCA1 BRCT repeats, which are a clinically important functional domain, and computational evidence supports a damaging effect rather than a benign one.

BP4 This variant does not meet the BRCA1 BP4 rule because it is a missense change within a clinically important domain and BayesDel is 0.398132, which is above the benign BP4 threshold of 0.15.

BP5 In the BRCA1 clinical-history likelihood-ratio table, this variant has an LR of 1.211619929099039 based on 1 proband.

BP7 This is a missense variant within the BRCA1 BRCT repeats.

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 (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 ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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