ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.7G>A (p.Gly3Arg) (rs376403182)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163662 SCV000214233 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);In silico models in agreement (benign)
Invitae RCV000228544 SCV000291247 uncertain significance Fanconi anemia, complementation group O 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 3 of the RAD51C protein (p.Gly3Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs376403182, ExAC 0.01%). This variant has been observed in individuals affected with breast/ovarian cancer (PMID: 20400964, 26261251, 26976419, 25470109), and an individual with head and neck squamous cell carcinoma (PMID: 24315737). ClinVar contains an entry for this variant (Variation ID: 184411). In vitro experimental studies using RAD51C-deficient cell lines have shown that RAD51C protein expressing this missense variant could complement mitomicyin C hypersensitivity and normal RAD51 foci formation following DNA damage (PMID: 20400964). 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.
GeneDx RCV000479892 SCV000567886 uncertain significance not provided 2017-06-22 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.7G>A at the cDNA level, p.Gly3Arg (G3R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has been observed in individuals with breast or ovarian cancer as well as in an individual with cancer of the larynx (Meindl 2010, Scheckenbach 2014, Song 2015, Tung 2016). In vitro analyses examining cell survival and RAD51 foci found this variant to behave similar to wild-type (Meindl 2010). RAD51C Gly3Arg was observed at an allele frequency of 0.012% (1/8,618) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Gly3Arg occurs at a position that is not conserved and is located in the region required for Holliday junction resolution activity (UniProt). 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 RAD51C Gly3Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000163662 SCV000679742 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color RCV000163662 SCV000902987 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-19 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV001195006 SCV001365238 likely benign not specified 2014-11-02 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.

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