Classification rationale

PS3PP3PP5 Likely Pathogenic

BRCA1 c.5089T>C

The BRCA1 c.5089T>C (p.Cys1697Arg) variant has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA expert panel and is listed in OncoKB as Likely Oncogenic with loss-of-function effect.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.² Calibrated BRCA1 functional studies compiled by ENIGMA show complete functional impact/loss of function for p.(Cys1697Arg), supporting PS3_Strong.³ The variant lies within the BRCA1 BRCT repeat region, has a BayesDel score of 0.398 which is above the PP3 threshold of 0.28, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, supporting PP3.⁴

PS3 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗oncokb ↗

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_18vcep_supplementarytables_v1_2_2024_11_18spliceai ↗

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_007294.4 · variants mapped to exon structure

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 14 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 · 3

Strength Supporting Moderate Strong Very strong

PS3 strong review Pathogenic

Calibrated BRCA1 functional studies show this variant has damaging loss-of-function effects. ENIGMA Table 9 assigns PS3_Strong to c.5089T>C based on three studies, and supplementary functional tables classify p.(Cys1697Arg) as having complete functional impact/loss of function.

ENIGMA Table 9 lists BRCA1 c.5089T>C p.(Cys1697Arg) as PS3 Strong.Table 9 cites three calibrated studies: Findlay 2018Petitalot 2019

cspec ↗

PP3 supporting review Pathogenic

This missense variant is located in the BRCA1 BRCT repeats (amino acids 1650-1857), has a BayesDel score of 0.398, which is above the ENIGMA PP3 threshold of 0.28, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08. These findings support a damaging protein effect consistent with PP3.

Variant protein position is Cys1697 within the BRCT repeats.Supplementary bioinformatic data show BayesDel 0.39813199999999999.ENIGMA PP3 threshold for missense variants in clinically important domains is BayesDel ≥0.28.

cspec ↗spliceai ↗

PP5 supporting review Pathogenic

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

ENIGMA BRCA1 v1.2 marks PP5 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

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

Pathogenic

PS1 No previously classified pathogenic variant with the same amino acid substitution was identified in the reviewed evidence, so PS1 was not applied.

PS4 The reviewed evidence does not provide a case-control analysis with p-value ≤0.05 and odds ratio ≥4 with the lower confidence interval excluding 2.0, so PS4 was not applied.

PM2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity, but the ENIGMA PM2 rule specifically requires absence in gnomAD v2.1 and v3.1 with average read depth ≥25, and those full coverage elements were not provided here.

PM3 No evidence was identified for biallelic BRCA1 disease or Fanconi anemia probands with qualifying co-occurring BRCA1 variants, so PM3 was not applied.

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

PP4 The BRCA1 clinical-history likelihood ratio for this variant is 1.21 in 1 proband, which is below the ENIGMA PP4 threshold of 2.08, so PP4 is not met.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BA1 threshold of filter allele frequency greater than 0.1%.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the BS1 thresholds of filter allele frequency above 0.002% or 0.01%.

BS2 No qualifying point-based evidence was identified from individuals without Fanconi anemia features, so BS2 was not applied.

BS3 Available calibrated functional studies do not show a neutral effect.

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

BP1 This missense variant is located within the BRCA1 BRCT repeats rather than outside a clinically important domain, and the BayesDel score is 0.398, which does not support a benign protein prediction.

BP4 Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, the BayesDel score is 0.398, which is above the benign threshold of 0.15.

BP5 The BRCA1 clinical-history likelihood ratio for this variant is 1.21 in 1 proband, which is above the ENIGMA BP5 threshold of 0.48 and falls in the neutral zone, so BP5 is not met.

N/A · 11 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6 · BP7

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).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely 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 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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