ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.1097G>A (p.Arg366Gln) (rs577852020)

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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 RCV000569753 SCV000671880 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000569753 SCV000691217 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000478660 SCV000568395 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.1097G>A at the cDNA level, p.Arg366Gln (R366Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant was observed in at least two individuals with a personal and family history of breast cancer (Meindl 2010, Gevensleben 2014). Tumor analysis from one of these individuals demonstrated no loss of heterozygosity, but the variant segregated with disease in two affected relatives (Meindl 2010). Results from a series of functional assays led Somyajit et al. (2015) to suggest RAD51C Arg366Gln may be a hypomorphic allele. In vitro studies demonstrated reduced homologous recombination activity compared to wild-type, as well as increased sensitivity to a PARP inhibitor (Somyajit 2015). RAD51C Arg366Gln was also shown to result in moderate sensitivity to DNA damaging agents, prolonged accumulation in G2/M phase with exposure to Mitomycin C, and a moderate increase in radical chromosome and chromatid breaks (Somyajit 2012, Somyajit 2015). However, this variant exhibited no significant difference in activation of CHK2 or association with XRCC2 (Somyajit 2015). RAD51C Arg366Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. RAD51C Arg366Gln occurs at a position that is not conserved and is located in nuclear localization signal motif and a region of interaction with RAD51B, RAD51D, and XRCC3 (French 2003, Miller 2004). 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 Arg366Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000648261 SCV000770075 uncertain significance Fanconi anemia, complementation group O 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 366 of the RAD51C protein (p.Arg366Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs577852020, ExAC 0.01%). This variant has been reported in several members from a single family affected with breast cancer; however, it was also detected in unaffected members of the family suggesting that this variant does not segregate with disease (PMID: 20400964). ClinVar contains an entry for this variant (Variation ID: 420041). Experimental studies have shown that this missense change results in reduced homologous recombination activity, a hypomorphic DNA damage response, and reduced binding to RAD51 and XRCC2 (PMID: 22167183, 20400964). There was no change in CHEK2 activation (PMID: 22167183). 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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