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LYFE SCIENCES
Project: HERA
NM_007294.4:c.191G>A
p.Cys64Tyr  ·  BRCA1
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Classification rationale
1

The BRCA1 c.191G>A (p.Cys64Tyr) variant has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA expert panel and by multiple clinical laboratories.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present at an extremely low frequency in gnomAD v4.1 (2/1,601,934 alleles; AF 1.24849e-06; highest observed subpopulation AF 1.61181e-05).

gnomad_v2 ↗ gnomad_v4 ↗
3

ENIGMA BRCA1 functional evidence assigns PS3 Strong for this variant, and supplementary functional datasets classify it as having complete functional impact or loss of function.

4

BRCA1 clinical-history likelihood-ratio data show LR 69.1 across 9 probands for this variant, exceeding the PP4 Strong threshold of 18.7.

PMID:31853058 ↗ cspec ↗
5

The variant lies in the BRCA1 RING domain and is predicted to be damaging by BayesDel no-AF 0.557106, which is above the ENIGMA PP3 threshold of 0.28; SpliceAI also predicts splice impact with a maximum delta score of 0.87.

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
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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
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.24849e-06; MAF= 0.00012%, 2/1601934 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.61181e-05; MAF= 0.00161%, 1/62042 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (22 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory) 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 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 possible splice impact for this variant (max delta score = 0.87).
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.
ResidueC64
Hotspots ↗