ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.29T>G (p.Met10Arg) (rs730881936)

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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 RCV000160930 SCV000217600 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000160930 SCV000909434 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing
GeneDx RCV000212930 SCV000211636 uncertain significance not provided 2018-02-09 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.29T>G at the cDNA level, p.Met10Arg (M10R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). This variant has been observed in at least one individual with ovarian cancer (Vuorela 2011). RAD51C Met10Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region required for Holliday junction resolution activity (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51C Met10Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000466866 SCV000550184 uncertain significance Fanconi anemia, complementation group O 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 10 of the RAD51C protein (p.Met10Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is present in population databases (rs730881936, ExAC 0.003%). This variant has been reported in an individual affected with ovarian cancer (PMID: 21750962). ClinVar contains an entry for this variant (Variation ID: 182841). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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