ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.778C>T (p.Arg260Trp) (rs374196453)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129567 SCV000184349 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-24 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000197556 SCV000255194 uncertain significance Fanconi anemia, complementation group O 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 260 of the RAD51C protein (p.Arg260Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs374196453, ExAC 0.01%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 141175). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507192 SCV000602146 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000589224 SCV000616845 uncertain significance not provided 2017-07-13 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.778C>T at the cDNA level, p.Arg260Trp (R260W) at the proteinlevel, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge,been published in the literature as pathogenic or benign. RAD51C Arg260Trpwas not observed at a significant allelefrequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek2016). Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Arg260Trp occurs at a position that is conserved across species and islocated in the region of interaction with RAD51B, RAD51D, and XRCC3 (Miller 2004). In silico analyses predict thatthis variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclearwhether RAD51C Arg260Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589224 SCV000699824 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.778C>T (p.Arg260Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 2/121402 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). This variant was found in one CRC patient in one study without strong evidence for causality (Yurgelun_CDH1_JCO_2017). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
GeneKor MSA RCV000129567 SCV000822173 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000129567 SCV001358238 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-13 criteria provided, single submitter clinical testing

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