ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.217G>A (p.Glu73Lys) (rs369946779)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167186 SCV000218022 uncertain significance Hereditary cancer-predisposing syndrome 2014-12-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000588922 SCV000698092 uncertain significance not provided 2016-05-27 criteria provided, single submitter clinical testing Variant summary: The RAD51D c.217G>A (p.Glu73Lys) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 2/121310 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). One clinical diagnostic laboratory/reputable database classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000475794 SCV000551382 uncertain significance Breast-ovarian cancer, familial 4 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 73 of the RAD51D protein (p.Glu73Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs369946779, ExAC 0.02%) but has not been reported in the literature in individuals with a RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 187455). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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