ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.541G>A (p.Val181Met) (rs876658678)

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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 RCV000218763 SCV000274252 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000484139 SCV000571723 uncertain significance not provided 2016-09-19 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.541G>A at the cDNA level, p.Val181Met (V181M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Val181Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. RAD51D Val181Met occurs at a position that is not conserved and is located in the ATPase domain (Kim 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether RAD51D Val181Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000694399 SCV000822843 uncertain significance Breast-ovarian cancer, familial 4 2018-03-15 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 181 of the RAD51D protein (p.Val181Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 230636). 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.

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