ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.355T>C (p.Cys119Arg) (rs201313861)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160945 SCV000214018 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000160945 SCV000910862 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000586341 SCV000211652 uncertain significance not provided 2018-10-23 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.355T>C at the cDNA level, p.Cys119Arg (C119R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant was identified in at least two individuals from BRCA1/2-negative families with breast and/or ovarian cancer, one BRCA1/2- and TP53-negative individual with early-onset breast cancer, as well as in two individuals with invasive ovarian cancer, but was also observed in healthy controls (Osher 2012, Guti?rrez-Enr?quez 2014, Song 2015, Penkert 2018). RAD51D Cys119Arg was observed at an allele frequency of 0.01% (3/34420) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the RAD51C binding domain (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51D Cys119Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586341 SCV000698099 uncertain significance not provided 2016-09-16 criteria provided, single submitter clinical testing Variant summary: The RAD51D c.355T>C (p.Cys119Arg) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 6/126740 control chromosomes at a frequency of 0.0000473, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). This variant has been reported in patients affected with BrC/OvC, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more evidence becomes available.
Invitae RCV000227224 SCV000287709 uncertain significance Breast-ovarian cancer, familial 4 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 119 of the RAD51D protein (p.Cys119Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs201313861, ExAC 0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 22415235, 24130102, 26261251), and in individuals affected with pancreatic ductal adenocarcinoma (PMID: 28767289). This variant is also known as c.415A>G (p.C139R) in the literature. ClinVar contains an entry for this variant (Variation ID: 182856). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
Mendelics RCV000709444 SCV000839188 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing

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