ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.878C>T (p.Ala293Val) (rs769732230)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166859 SCV000217674 likely benign Hereditary cancer-predisposing syndrome 2017-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000166859 SCV000902927 likely benign Hereditary cancer-predisposing syndrome 2016-02-29 criteria provided, single submitter clinical testing
GeneDx RCV000656965 SCV000292683 uncertain significance not provided 2018-06-26 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.878C>T at the cDNA level, p.Ala293Val (A293V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). In a case-control study, this variant was absent from 3429 ovarian cancer cases but was identified in 1/2772 control individuals (Song 2015). RAD51D Ala293Val was observed at an allele frequency of 0.01% (2/18,868) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the RAD51C binding domain (Miller 2004). While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict creation of a novel weak cryptic donor site created upstream of the natural splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether RAD51D Ala293Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000232983 SCV000287728 uncertain significance Breast-ovarian cancer, familial 4 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 293 of the RAD51D protein (p.Ala293Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs769732230, ExAC 0.02%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 187161). 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 valine 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235380 SCV000602169 uncertain significance not specified 2017-04-19 criteria provided, single submitter clinical testing

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