ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.869G>A (p.Arg290Gln) (rs773883374)

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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 RCV000216468 SCV000275156 likely benign Hereditary cancer-predisposing syndrome 2018-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000216468 SCV000903446 likely benign Hereditary cancer-predisposing syndrome 2015-12-10 criteria provided, single submitter clinical testing
GeneDx RCV000485412 SCV000568984 uncertain significance not provided 2018-06-08 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.869G>A at the cDNA level, p.Arg290Gln (R290Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Arg290Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. RAD51D Arg290Gln 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 Arg290Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000230122 SCV000287727 uncertain significance Breast-ovarian cancer, familial 4 2018-08-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 290 of the RAD51D protein (p.Arg290Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases ( ExAC 0.01%) but has not been reported in the literature in individuals with a RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 231338). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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