NM_007294.4:c.191G>A

BRCA1 · NP_009225.1:p.(Cys64Tyr) · NM_007294.4

GRCh37: chr17:41258494 C>T · GRCh38: chr17:43106477 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

PS3_Strong PP4_Strong PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Cys64Tyr)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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).

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.

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

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.

Final determination: Pathogenic based on 2 Strong and 2 Supporting pathogenic criteria under the ENIGMA BRCA1/2 Table 3 combining rules.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, not a nonsense, frameshift, canonical +/-1,2 splice, initiation-codon, or exon-level loss-of-function variant, so PVS1 is not applicable.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	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.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	PS2 is not used in the ENIGMA BRCA1 specification.	cspec
PS3	Met	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.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not assessed	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.	clinvar cspec vcep_specifications_v1_2_2024_11_18
PM1	N/A	PM1 is not used in the ENIGMA BRCA1 specification.	cspec
PM2	Not met	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.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	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.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	PM4 is not used in the ENIGMA BRCA1 specification.	cspec
PM5	N/A	Under the ENIGMA BRCA1 specification, PM5 is used for protein-termination variants in exons where a different pathogenic protein-termination variant has been observed; this missense variant does not meet that variant-type requirement.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PP1	Not assessed	No quantitative co-segregation analysis meeting ENIGMA thresholds was identified, so PP1 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PP2	N/A	PP2 is not used in the ENIGMA BRCA1 specification.	cspec
PP3	Met	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.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18
PP4	Met	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.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	The variant frequency is well below the BA1 threshold of 0.001. In gnomAD v4.1 the total AF is 1.24849e-06 and the highest observed subpopulation AF is 1.61181e-05, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	The variant frequency is below both BS1 thresholds. The highest observed subpopulation AF in gnomAD v4.1 is 1.61181e-05, which is below 0.00002 for BS1 Supporting and below 0.0001 for BS1 Strong, so BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No ENIGMA point-based evidence from unaffected individuals without Fanconi anemia features was identified for this variant, so BS2 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
BS3	Not met	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.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation analysis meeting ENIGMA BS4 thresholds was identified for this variant, so BS4 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
BP1	Not met	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.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18
BP2	N/A	BP2 is not used in the ENIGMA BRCA1 specification.	cspec
BP3	N/A	BP3 is not used in the ENIGMA BRCA1 specification.	cspec
BP4	Not met	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. BP4 is therefore not met.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18
BP5	Not met	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.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	BP6 is not used in the ENIGMA BRCA1 specification.	cspec
BP7	Not met	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.	cspec vcep_specifications_table9_v1_2_2024_11_18
PM6	N/A	PM6 is not used in the ENIGMA BRCA1 specification.	cspec

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