ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.868C>T (p.Arg290Trp) (rs527964137)

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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 RCV000166995 SCV000217816 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000457545 SCV000551371 uncertain significance Breast-ovarian cancer, familial 4 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 290 of the RAD51D protein (p.Arg290Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs527964137, 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: 187277). 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 tryptophan 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. 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.
GeneDx RCV000589564 SCV000570460 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.868C>T at the cDNA level, p.Arg290Trp (R290W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. RAD51D Arg290Trp 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 Arg290Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589564 SCV000698115 uncertain significance not provided 2015-12-07 criteria provided, single submitter clinical testing Variant summary: variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a large size and aromatic Tryptophan (W). 3/4 in silico tools predict neutral outcome for this substitution (SNPs&GO was not considered because of the low reliability index). Variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.0049% which does not exceed the maximal expected allele frequency of a disease causing RAD51D allele (0.025%). To our knowledge, the variant was not reported in HBOC spectrum patients and in vitro/vivo studies assessing the functional impact of the variant were not published either at the time of scoring. Due to lack of clinical data and functional studies, the variant was classified as a variant of uncertain significance until more information becomes available.
Color RCV000166995 SCV000908945 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-21 criteria provided, single submitter clinical testing

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