ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.871C>T (p.Arg291Cys) (rs372038369)

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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 RCV000216279 SCV000274921 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000475686 SCV000551342 uncertain significance Breast-ovarian cancer, familial 4 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 291 of the RAD51D protein (p.Arg291Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs372038369, ExAC 0.01%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 231161). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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.
Color RCV000216279 SCV000908944 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001174934 SCV001338383 uncertain significance not specified 2020-02-24 criteria provided, single submitter clinical testing Variant summary: RAD51D c.871C>T (p.Arg291Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251390 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.871C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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