The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!


Variant: NM_007294.4(BRCA1):c.5089T>C (p.Cys1697Arg)

CA003228

55392 (ClinVar)

Gene: BRCA1
Condition: BRCA1-related cancer predisposition
Inheritance Mode: Autosomal dominant inheritance
UUID: f967f72f-9e0d-4402-8841-91c26c03b30f
Approved on: 2024-06-12
Published on: 2024-06-12

HGVS expressions

NM_007294.4:c.5089T>C
NM_007294.4(BRCA1):c.5089T>C (p.Cys1697Arg)
NC_000017.11:g.43063937A>G
CM000679.2:g.43063937A>G
NC_000017.10:g.41215954A>G
CM000679.1:g.41215954A>G
NC_000017.9:g.38469480A>G
NG_005905.2:g.154047T>C
ENST00000461574.2:c.5086T>C
ENST00000470026.6:c.5089T>C
ENST00000473961.6:c.4963T>C
ENST00000476777.6:c.5083T>C
ENST00000477152.6:c.5011T>C
ENST00000478531.6:c.1777T>C
ENST00000489037.2:c.5011T>C
ENST00000493919.6:c.1639T>C
ENST00000494123.6:c.5089T>C
ENST00000497488.2:c.4201T>C
ENST00000618469.2:c.5089T>C
ENST00000634433.2:c.4966T>C
ENST00000644379.2:c.5155T>C
ENST00000644555.2:c.1639T>C
ENST00000652672.2:c.4948T>C
ENST00000484087.6:c.1651T>C
ENST00000357654.9:c.5089T>C
ENST00000471181.7:c.5152T>C
ENST00000644379.1:c.1476T>C
ENST00000352993.7:c.1663T>C
ENST00000357654.7:c.5089T>C
ENST00000461221.5:c.*4872T>C
ENST00000468300.5:c.1777T>C
ENST00000471181.6:c.5152T>C
ENST00000478531.5:c.1777T>C
ENST00000484087.5:c.1402T>C
ENST00000491747.6:c.1777T>C
ENST00000493795.5:c.4948T>C
ENST00000493919.5:c.1639T>C
ENST00000586385.5:c.19T>C
ENST00000591534.5:c.562T>C
ENST00000591849.5:c.-98-13747T>C
NM_007294.3:c.5089T>C
NM_007297.3:c.4948T>C
NM_007298.3:c.1777T>C
NM_007299.3:c.1777T>C
NM_007300.3:c.5152T>C
NR_027676.1:n.5225T>C
NM_007297.4:c.4948T>C
NM_007299.4:c.1777T>C
NM_007300.4:c.5152T>C
NR_027676.2:n.5266T>C

Pathogenic

Met criteria codes 5
PS3 PP3 PP4_Strong PP1_Moderate PM2_Supporting

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
ENIGMA BRCA1 and BRCA2 VCEP
The c.5089T>C variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 1697 (p.Cys1697Arg). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.40, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.05 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met). Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 5.24, within the thresholds for moderate pathogenic evidence (LR >4.3 & ≤18.7) (PP1_Moderate met; internal lab contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2735.2 (based on Cosegregation LR=730.6; Pathology LR=2.41; Family History LR=1.56), above the thresholds for Very strong evidence towards pathogenicity (LR>350) (PP4_Very strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP1_Moderate, PP4_Very strong).
Met criteria codes
PS3
Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met).

PP3
This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.40, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.05 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met).
PP4_Strong
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2735.2 (based on Cosegregation LR=730.6; Pathology LR=2.41; Family History LR=1.56), above the thresholds for Very strong evidence towards pathogenicity (LR>350) (PP4_Very strong met; PMID: 31131976).
PP1_Moderate
Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 5.24, within the thresholds for moderate pathogenic evidence (LR >4.3 & ≤18.7) (PP1_Moderate met; internal lab contributor).
PM2_Supporting
This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met).
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