ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.793G>A (p.Gly265Arg) (rs140285068)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130963 SCV000185878 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130963 SCV000911208 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000233452 SCV000895088 uncertain significance Breast-ovarian cancer, familial 4 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000679541 SCV000292760 uncertain significance not provided 2017-02-08 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.793G>A at the cDNA level, p.Gly265Arg (G265R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). RAD51D Gly265Arg has been reported in familial breast and ovarian cancer, but has demonstrated incomplete segregation and has also been observed in control subjects (Loveday 2011, Osher 2012, Thompson 2013, Song 2015). RAD51D Gly265Arg was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51D Gly265Arg occurs at a position that is conserved across species and is located in the RAD51C binding domain (Miller 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether RAD51D Gly265Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233452 SCV000287725 uncertain significance Breast-ovarian cancer, familial 4 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 265 of the RAD51D protein (p.Gly265Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs140285068, ExAC 0.01%). This variant has been reported in at least one individual with breast cancer as well as in a family from a hereditary breast and ovarian cancer study in which the variant reportedly did not segregate with disease (PMID: 23372765, 22415235). This variant has also been reported in three unaffected individuals (PMID: 26261251, 21822267). It is also known as c.853G>A (p.Gly285Arg) in the literature. ClinVar contains an entry for this variant (Variation ID: 142125). 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 disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000709435 SCV000839177 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000679541 SCV000806587 uncertain significance not provided 2017-08-08 criteria provided, single submitter clinical testing

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