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LYFE SCIENCES
Project: HERA
NM_007294.4:c.131G>A
p.Cys44Tyr  ·  BRCA1
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Classification rationale
1

The BRCA1 c.131G>A (p.Cys44Tyr) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including ENIGMA expert panel review.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

gnomad_v2 ↗ gnomad_v4 ↗
3

Calibrated functional studies have shown a damaging loss-of-function effect for p.Cys44Tyr, and ENIGMA BRCA1 Table 9 assigns PS3_Strong based on these data.

4

The missense change affects the BRCA1 RING domain, a clinically important functional domain, with BayesDel 0.57077 supporting deleterious impact, while SpliceAI predicts no meaningful splice effect (max delta 0.01).

spliceai ↗
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
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Oncogenic
OncoKB classifies this variant as Oncogenic; biological effect: Loss-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107367559, n = 1 times).
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueC44
Hotspots ↗