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.1 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).2 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.3 BRCA1 clinical-history likelihood-ratio data show LR 69.1 across 9 probands for this variant, exceeding the PP4 Strong threshold of 18.7.4 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 0.87.5
BRCA1
Final classification
Pathogenic
BRCA1 c.191G>A · p.Cys64Tyr
BRCA1
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.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework (criteria combination)
Classification rationale
PS3PP3PP4PP5
Pathogenic
BRCA1 c.191G>A
PS3 + PP3 + PP4 + PP5
→
Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001
4
PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lrcspec ↗
5
vcep_supplementarytables_v1_2_2024_11_18spliceai ↗cspec ↗
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This 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).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,601,934
0 hom
0 hom
Remaining individuals 1 / 62,042 |
0.0016% |
European (non-Finnish) 1 / 1,170,064 |
8.5e-05% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.87).
Functional
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.
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.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:30209399
Found
Structured finding pending for this record — see source link.
Applied to
→PP3 supports · met
→PS3 supports · met
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
Sources & reference links