ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.185C>T (p.Ser62Leu) (rs374357106)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164390 SCV000215026 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-25 criteria provided, single submitter clinical testing The p.S62L variant (also known as c.185C>T), located in coding exon 3 of the RAD51D gene, results from a C to T substitution at nucleotide position 185. The serine at codon 62 is replaced by leucine, an amino acid with dissimilar properties. In one study, this variant was detected in 1/911 patients from families with breast and/or ovarian cancer and was not seen in 1060 population controls from the United Kingdom (Loveday C et al. Nat. Genet., 2011 Aug;43:879-882). In another study, this variant was not detected in 3429 patients with invasive epithelial ovarian cancer, but was reported in 1/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000236527 SCV000292802 uncertain significance not provided 2018-12-03 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.185C>T at the cDNA level, p.Ser62Leu (S62L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant was observed in two series investigating families with breast and/or ovarian cancer, with observation in one case and one control (Loveday 2011, Song 2015). RAD51D Ser62Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the XRCC2 binding domian (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51D Ser62Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000461972 SCV000551366 uncertain significance Breast-ovarian cancer, familial 4 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 62 of the RAD51D protein (p.Ser62Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs374357106, ExAC 0.006%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 185036). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000164390 SCV000686424 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-18 criteria provided, single submitter clinical testing

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