ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2840T>C (p.Ile947Thr) (rs150401251)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212922 SCV000149858 uncertain significance not provided 2016-07-19 criteria provided, single submitter clinical testing RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.2840T>C at the cDNA level, p.Ile947Thr (I947T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Ile947Thr was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution and is likely to affect protein integrity. RAD50 Ile947Thr occurs at a position that is well conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Ambry Genetics RCV000115949 SCV000184404 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000115949 SCV000254895 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 947 of the RAD50 protein (p.Ile947Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs150401251, ExAC 0.009%). This variant has been reported in the literature in an individual affected with lung adenocarcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 128013). 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: "Benign"; 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.
Counsyl RCV000410140 SCV000488874 uncertain significance Nijmegen breakage syndrome-like disorder 2016-07-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194193 SCV001363538 uncertain significance not specified 2019-02-14 criteria provided, single submitter clinical testing Variant summary: RAD50 c.2840T>C (p.Ile947Thr) 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 7.6e-05 in 274800 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00014 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), suggesting that the variant might be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2840T>C has been reported in the literature in an individual affected with lung adenocarcinoma (Lu 2015). This report does 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. 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 VUS-possibly benign.

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