ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.259C>T (p.Arg87Cys) (rs143802516)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164239 SCV000214862 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000164239 SCV000259547 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 87 of the RAD50 protein (p.Arg87Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs143802516, ExAC 0.04%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 184899). 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 and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV000781780 SCV000920105 uncertain significance not specified 2018-10-01 criteria provided, single submitter clinical testing Variant summary: RAD50 c.259C>T (p.Arg87Cys) results in a non-conservative amino acid change located in the Rad50/SbcC-type AAA domain of the encoded protein sequence. Three 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 277052 control chromosomes, predominantly at a frequency of 0.00033 within the African subpopulation in the gnomAD database. This frequency exceeds the maximal expected allele frequency for a disease causing allele in RAD50 gene (0.00006), suggesting that this variant may represent a rare ethnic polymorphism. To our knowledge, no occurrence of c.259C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.

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