ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.973G>A (p.Gly325Ser) (rs587780106)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571425 SCV000663814 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000571425 SCV000686508 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000656968 SCV000149733 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.973G>A at the cDNA level, p.Gly325Ser (G325S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant has been observed in at least one individual undergoing cancer panel testing due to a history suggestive of Lynch syndrome (Yurgelun 2015). RAD51D Gly325Ser 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 Gly325Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000115824 SCV000918137 uncertain significance not specified 2018-03-28 criteria provided, single submitter clinical testing Variant summary: RAD51D c.973G>A (p.Gly325Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246270 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer (8.1e-06 vs 0.00013), allowing no conclusion about variant significance. c.973G>A has been reported in the literature in affected individuals (Tung 2014, Yurgelun 2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000554021 SCV000651798 uncertain significance Breast-ovarian cancer, familial 4 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 325 of the RAD51D protein (p.Gly325Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127898). 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.
Mendelics RCV000709426 SCV000839168 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115824 SCV000602172 uncertain significance not specified 2017-03-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656968 SCV000888616 uncertain significance not provided 2018-05-21 criteria provided, single submitter clinical testing

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