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LYFE SCIENCES
Project: HERA
NM_007294.3:c.5089T>C
p.Cys1697Arg  ·  BRCA1
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Classification rationale
1

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.

clinvar ↗
2

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

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

4

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.

cspec ↗ 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 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 ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
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 ↗
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 ↗