ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2750C>T (p.Thr917Ile) (rs562172843)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212921 SCV000149856 uncertain significance not provided 2014-02-26 criteria provided, single submitter clinical testing RAD50 has only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.2750C>T at the cDNA level, p.Thr917Ile (T917I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Thr917Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution and is likely to affect secondary protein structure. RAD50 Thr917Ile occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or 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 RCV000115947 SCV000186577 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000115947 SCV000628221 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 917 of the RAD50 protein (p.Thr917Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs562172843, ExAC 0.05%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 128011). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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