ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.70T>C (p.Cys24Arg) (rs80357410)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000111679 SCV000326399 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586566 SCV000699296 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-11 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.70T>C (p.Cys24Arg) variant involves the alteration of a conserved nucleotide resulting in a replacement of a conserved canonical Cysteine residue of the BRCA1 domain with an Arginine. Cysteine residues are known to be essential for Zn ion coordination and for proper folding of the RING domain of the BRCA1 protein (PMID: 11573085). Mutations of these Cysteine residues are known to be clinically relevant, and predispose individuals to cancer (BIC, HGMD). Consistently, 5/5 in silico tool predict this variant to be deleterious. Furthermore, it is absent in 120972 control chromosomes. It was reported by the BIC database in two affected members of a family further supporting its pathogenicity. Multiple independent functional studies have demonstrated that this variant results in a loss of homology directed repair activity of BRCA1 in addition to a loss of E3 ubiquitin ligase activity as well as its ability to bind to the RING domain of the BARD1 protein. A congruence of multiple functional studies further supports a disease causing impact for this variant. Two databases classify variant as Pathogenic (UMD, HGMD) while ClinVar lists this variant as Uncertain dating back to an evaluation performed in 2002 prior to the publications reporting multiple functional impacts. Considering all available lines of evidence, the variant is classified as Likely Pathogenic variant in the BRCA1 gene.
Invitae RCV000586566 SCV001587501 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 24 of the BRCA1 protein (p.Cys24Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with increased risk of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 55674). This variant has been reported to affect BRCA1 protein function (PMID: 25823446, 21725363, 24489791, 11320250, 23161852). This variant disrupts the p.Cys24 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18489799, 24249303, 29176636, 25823446, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111679 SCV000144179 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000111679 SCV001243733 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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