ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.865G>A (p.Gly289Ser) (rs587782129)

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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 RCV000130672 SCV000185558 likely benign Hereditary cancer-predisposing syndrome 2015-10-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other strong data supporting benign classification
Invitae RCV000462688 SCV000551343 uncertain significance Breast-ovarian cancer, familial 4 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 289 of the RAD51D protein (p.Gly289Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs587782129, ExAC 0.002%) but has not been reported in the literature in individuals with a RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 141945). 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.
GeneDx RCV000480701 SCV000569950 uncertain significance not provided 2016-04-12 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.865G>A at the cDNA level, p.Gly289Ser (G289S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Gly289Ser 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 Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51D Gly289Ser occurs at a position that is not conserved and is located in the ATPase domain (Kim 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether RAD51D Gly289Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130672 SCV000908946 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing

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