ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.872G>A (p.Arg291His) (rs150134822)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160954 SCV000218011 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000160954 SCV000686493 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000590323 SCV000211661 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.872G>A at the cDNA level, p.Arg291His (R291H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been identified in at least one individual with family history of breast/ovarian cancer, but has also been observed in healthy controls (Loveday 2011, Song 2015). RAD51D Arg291His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 Arg291His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590323 SCV000698116 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The RAD51D c.872G>A (p.Arg291His) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 7/128950 control chromosomes at a frequency of 0.0000543, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). The variant was reported in the literature in both case and controls, without strong evidence for causality (Loveday_2011, Song_2015).In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000205359 SCV000262193 uncertain significance Breast-ovarian cancer, familial 4 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 291 of the RAD51D protein (p.Arg291His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs150134822, ExAC 0.009%). This variant has been observed in an individual affected with breast or ovarian cancer (PMID: 21822267) and in unaffected individuals (PMID: 21822267, 26261251). ClinVar contains an entry for this variant (Variation ID: 182865). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000590323 SCV000888612 uncertain significance not provided 2018-08-06 criteria provided, single submitter clinical testing

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