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
Final classification
Pathogenic
PS3PP3PP4PP5
BRCA1
c.191G>A
p.Cys64Tyr
This variant
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 ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
review
Pathogenic
ENIGMA BRCA1 Table 9 assigns PS3 Strong for this variant because a calibrated functional study reported protein function similar to pathogenic control variants, and supplementary functional datasets classify the variant as having complete functional impact or loss of function.
Table 9 entry: BRCA1 c.191G>A p.(Cys64Tyr) -> PS3 StrongST4: Functional impact - complete / LOFSuppT4: functional assay data support complete impact
PP3
supporting
review
Pathogenic
This missense variant is located in the BRCA1 RING domain, and the reviewed bioinformatic evidence supports a deleterious effect: BayesDel no-AF is 0.557106, which is above the ENIGMA PP3 threshold of 0.28, and SpliceAI predicts splice impact with a maximum delta score of 0.87, which is above the splice threshold of 0.2.
RING domain locationBayesDel noAF 0.557106SpliceAI max delta 0.87
PP4
strong
review
Pathogenic
BRCA1 clinical-history likelihood-ratio data show an LR of 69.10003048643809 across 9 probands for this variant, which is above the ENIGMA PP4 Strong threshold of 18.7 and supports pathogenicity.
clinical-history LR 69.10003048643809N probands 9PP4 Strong threshold 18.7
Assessed · not applied
· 8 not met · 6 not assessed
Pathogenic
PS1
No evidence was identified here showing that a different nucleotide change causing the same amino acid substitution or the same splicing outcome has already been classified as pathogenic or likely pathogenic under the ENIGMA BRCA1 rules.
PS4
This variant has been reported in affected individuals, but no case-control analysis with p-value <=0.05 and odds ratio >=4 with the lower confidence interval excluding 2.0 was identified here, so PS4 was not assessed.
PM2
This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at a very low frequency (2/1,601,934 alleles; AF 1.24849e-06; highest observed subpopulation AF 1.61181e-05), so the strict absence-from-controls requirement for PM2 is not met.
PM3
No evidence was identified for biallelic BRCA1 disease with a Fanconi-anemia-consistent phenotype and an ENIGMA point assignment for this variant, so PM3 was not assessed.
PP1
No quantitative co-segregation analysis meeting ENIGMA thresholds was identified, so PP1 was not assessed.
Benign
BA1
The variant frequency is well below the BA1 threshold of 0.001.
BS1
The variant frequency is below both BS1 thresholds.
BS2
No ENIGMA point-based evidence from unaffected individuals without Fanconi anemia features was identified for this variant, so BS2 was not assessed.
BS3
Although mRNA studies reported no aberration, the calibrated ENIGMA BRCA1 functional summary for this variant assigns PS3 Strong and the supplementary functional datasets classify the variant as complete functional impact or loss of function, so benign functional evidence is not supported.
BS4
No quantitative lack-of-segregation analysis meeting ENIGMA BS4 thresholds was identified for this variant, so BS4 was not assessed.
BP1
This missense variant is located in the BRCA1 RING domain, which is a clinically important functional domain, and the predictive evidence does not show no-splicing-impact because SpliceAI is 0.87, above the <=0.1 threshold; therefore BP1 is not met.
BP4
This missense variant is in the BRCA1 RING domain, but the predictive evidence does not support a benign effect: BayesDel no-AF is 0.557106, which is above the BP4 benign threshold of <=0.15, and SpliceAI is 0.87, which is above the <=0.1 threshold.
BP5
The clinical-history likelihood ratio for this variant is 69.10003048643809 in the pathogenic direction, which is well above the benign BP5 thresholds of <=0.48, <=0.23, and <=0.05, so BP5 is not met.
BP7
mRNA studies reported no aberration, but this missense variant lies within the BRCA1 RING domain and ENIGMA requires BS3 for BP7_Strong RNA in this setting; because BS3 is not supported and the functional evidence supports damage, BP7 is not met.
N/A · 10
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6
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 30209399
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
→PP3
supporting
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→PP4
strong
Sources & reference links