ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.340G>A (p.Gly114Arg) (rs786203690)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167106 SCV000217936 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
GeneDx RCV000586168 SCV000573112 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.340G>A at the cDNA level, p.Gly114Arg (G114R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. RAD51C Gly114Arg 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 as well as in the region of interaction with RAD51B, RAD51D, and XRCC3 (Miller 2004, 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 Gly114Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000167106 SCV000686343 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586168 SCV000699805 uncertain significance not provided 2017-03-16 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.340G>A (p.Gly114Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120888 control chromosomes. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000793970 SCV000933352 uncertain significance Fanconi anemia, complementation group O 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 114 of the RAD51C protein (p.Gly114Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD51C-related disease. ClinVar contains an entry for this variant (Variation ID: 187382). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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