Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590262 | SCV000698860 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2016-05-13 | criteria provided, single submitter | clinical testing | Variant summary: The BRCA1 c.139T>G (p.Cys47Gly) variant involves the alteration of a conserved nucleotide resulting in a replacement of a conserved canonical Cysteine residue of the BRCA1 RING domain with a Glycine. 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 tools predict this variant to be deleterious. Furthermore, it is absent in 111676 control chromosomes. It was reported in one early onset TNBC patient further supporting its pathogenicity. Multiple independent functional studies have demonstrated that this variant results in 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 UbcH5a protein. A congruence of multiple functional studies further supports a disease causing impact for this variant. Two databases classify variant as Pathogenic (UMD, HGMD). Moreover, BIC, HGMD, ClinVar list variants affecting the same codon as the variant of interest (C47F, C47Y, C47X) as pathogenic indicating the variant to be located in a mutational hotspot and further supporting a disease causing impact. Considering all available lines of evidence, the variant is classified as a Probably Disease causing (i.e., Likely Pathogenic) variant in the BRCA1 gene. |
| Breast Cancer Information Core |
RCV000111868 | SCV000144445 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion criteria provided | clinical testing | ||
| Brotman Baty Institute, |
RCV000111868 | SCV001242936 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |