ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.14C>T (p.Thr5Met) (rs201523760)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590726 SCV000150081 uncertain significance not provided 2018-08-31 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.14C>T at the cDNA level, p.Thr5Met (T5M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant was identified in an individual with clear cell renal cancer (Lu 2015). Song et al. (2015) did not identify this variant in 3429 ovarian cancer cases but identified it in 1/2772 controls. RAD51C Thr5Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the region required for Holliday junction resolution activity (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51C Thr5Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000123370 SCV000166693 uncertain significance Fanconi anemia, complementation group O 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 5 of the RAD51C protein (p.Thr5Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs201523760, ExAC 0.009%). This variant has been reported in an individual affected with kidney cancer (PMID: 26689913), as well as an unaffected control individual (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 128203). 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 tolerated, but these predictions have not been confirmed by published functional 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.
Ambry Genetics RCV000116172 SCV000217272 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Counsyl RCV000123370 SCV000489939 uncertain significance Fanconi anemia, complementation group O 2016-08-16 criteria provided, single submitter clinical testing
Counsyl RCV000411171 SCV000489940 uncertain significance Breast-ovarian cancer, familial 3 2016-08-16 criteria provided, single submitter clinical testing
Color RCV000116172 SCV000537604 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590726 SCV000699796 uncertain significance not provided 2016-03-14 criteria provided, single submitter clinical testing Variant summary: This RAD51C variant affects a non-conserved nucleotide and results in a replacement of a medium size and polar Threonine (T) medium size and hydrophobic Methionine (M). 3/4 in silico tools predict the variant to be neutral. It was observed exclusively in the Non-Finnish European subcohorts of the ExAC project at an allele frequency of 0.009% which exceeds, by 1.4 times, the maximal expected allele frequency of disease causing RAD51C (0.0062%), indicating neutrality. However, the penetrance of RAD51C variants are variable, therefore the population data has to be taken with caution. To our knowledge, the variant has not been reported in HBOC spectrum patients, but was identified in a kidney renal clear cell carcinoma, and studies assessing the functional impact of the variant on protein function were not published at the time of variant classification. Several clinical diagnostic laboratories classify variant as Uncertain via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as a variant of uncertain significance until more information becomes available.

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