ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.802T>A (p.Trp268Arg) (rs755965977)

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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 RCV000216827 SCV000278522 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000216827 SCV000686489 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing
GeneDx RCV000480783 SCV000566432 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.802T>A at the cDNA level, p.Trp268Arg (W268R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>AGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. RAD51D Trp268Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the RAD51C binding domain (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 Trp268Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000532411 SCV000651782 uncertain significance Breast-ovarian cancer, familial 4 2018-12-15 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 268 of the RAD51D protein (p.Trp268Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs755965977, ExAC 0.009%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 234037). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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