ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.956G>A (p.Arg319Gln) (rs367846829)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526400 SCV000660372 uncertain significance Fanconi anemia, complementation group O 2019-04-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 319 of the RAD51C protein (p.Arg319Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs367846829, ExAC 0.01%). This variant has been reported in an individual affected with ovarian cancer, and in a healthy control individual (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 478615). 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 glutamine 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.
Ambry Genetics RCV000561452 SCV000664917 likely benign Hereditary cancer-predisposing syndrome 2019-03-30 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
Color RCV000561452 SCV000909736 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781791 SCV000920118 uncertain significance not specified 2019-02-12 criteria provided, single submitter clinical testing Variant summary: The variant, RAD51C c.956G>A (p.Arg319Gln) results in a conservative amino acid change located in the C-terminal domain (IPR013632) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 246074 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.956G>A, has been reported in the literature in a patient affected with epithelial ovarian cancer, but was also found in a healthy control individual (Song 2015). This report does 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory has classified the variant as likely benign, and the other as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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