ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.1096C>T (p.Arg366Trp) (rs587782449)

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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 RCV000131519 SCV000186513 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing in silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or Conflicting Evidence;Rarity in general population databases (dbSNP, ESP, 1000 Genomes)
Invitae RCV000168209 SCV000218874 uncertain significance Fanconi anemia, complementation group O 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 366 of the RAD51C protein (p.Arg366Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with breast and/or ovarian cancer (PMID: 26740214). ClinVar contains an entry for this variant (Variation ID: 142416). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000236993 SCV000293630 uncertain significance not provided 2018-02-26 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.1096C>T at the cDNA level, p.Arg366Trp (R366W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been observed in at least one breast cancer patient (J?nson 2016). RAD51C Arg366Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Arg366Trp is located in the nuclear localization signal and the region required for interaction with RAD51B, RAD51D, XRCC3 (French 2003, Miller 2004). 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 Arg366Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131519 SCV000686319 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236993 SCV000889813 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780671 SCV000918130 uncertain significance not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: RAD51C c.1096C>T (p.Arg366Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 30974 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1096C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Jonson_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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