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

dbSNP: rs80357410

Total submissions: 7

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, susceptibility to, 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 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 ovarian cancer syndrome	2020-10-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. This variant has been reported to affect BRCA1 protein function (PMID: 25823446, 21725363, 24489791, 11320250, 23161852). 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 is not present in population databases (ExAC no frequency). 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.
Ambry Genetics	RCV002362685	SCV002663121	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-27	criteria provided, single submitter	clinical testing	The p.C24R pathogenic mutation (also known as c.70T>C), located in coding exon 1 of the BRCA1 gene, results from a T to C substitution at nucleotide position 70. The cysteine at codon 24 is replaced by arginine, an amino acid with highly dissimilar properties. This variant is non-functional in multiple assays including a BARD1 binding assay, a E3 Ubiquitin Ligase activity assay, a homology-directed repair assay, and a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222, Starita LM et al. Genetics, 2015 Jun;200:413-22, Towler WI et al. Hum. Mutat., 2013 Mar;34:439-45). Based on internal structural assessment, this alteration disrupts one of the Zn-binding sites of the BRCA1 RING domain (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7). Multiple pathogenic alterations are located at this position highlighting its sensitivity to amino acid substitution (Ambry internal data). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000111679	SCV004217019	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-12-08	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111679	SCV000144179	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111679	SCV001243733	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro