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LYFE SCIENCES
Project: HERA
NM_007294.4:c.5090G>A
p.Cys1697Tyr  ·  BRCA1
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Classification rationale
1

The BRCA1 c.5090G>A (p.Cys1697Tyr; C1697Y) variant has been reported in ClinVar as likely pathogenic by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, with additional clinical-laboratory submissions including likely pathogenic, pathogenic, and uncertain significance.

clinvar ↗
2

This variant is absent from the retrieved gnomAD v2.1 and gnomAD v4.1 population datasets, supporting PM2 at Supporting strength and arguing against BA1 or BS1 frequency-based benign evidence.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Calibrated ENIGMA functional evidence reports BRCA1 c.5090G>A p.(Cys1697Tyr) as PS3 Strong, with supplementary functional data recording complete functional impact and loss-of-function behavior.

4

The variant affects residue 1697 within the BRCA1 BRCT repeats, a clinically important domain, has BayesDel no-AF approximately 0.386-0.39 above the ENIGMA PP3 threshold of ≥0.28, and has SpliceAI max delta 0.03 below the predicted splice-impact threshold.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (3 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueC1697
Hotspots ↗