ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.785T>G (p.Leu262Arg) (rs201728859)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164729 SCV000215401 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000164729 SCV000254908 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 262 of the RAD50 protein (p.Leu262Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs201728859, ExAC 0.01%). This variant has been observed in individuals affected with breast cancer (PMID: 25452441, 26787654). ClinVar contains an entry for this variant (Variation ID: 185329). 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: "Tolerated"; PolyPhen-2: "Possibly 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.
GeneKor MSA RCV000164729 SCV000822161 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764575 SCV000895666 uncertain significance Nijmegen breakage syndrome-like disorder 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194194 SCV001363539 uncertain significance not specified 2019-01-15 criteria provided, single submitter clinical testing Variant summary: RAD50 c.785T>G (p.Leu262Arg) results in a non-conservative amino acid change in 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 5.4e-05 in 276126 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer (5.4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.785T>G has been reported in the literature in individuals affected with Breast Cancer (Damiola_2014, Couch_2015, Young_2016, Goidescu_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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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