ClinVar Miner

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

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Total submissions: 4
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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 2018-09-04 criteria provided, single submitter clinical testing The p.T917I variant (also known as c.2750C>T), located in coding exon 17 of the RAD50 gene, results from a C to T substitution at nucleotide position 2750. The threonine at codon 917 is replaced by isoleucine, an amino acid with similar properties. <span style="background-color:initial">This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000115947 SCV000628221 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-26 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174753 SCV001338070 uncertain significance not specified 2020-01-13 criteria provided, single submitter clinical testing Variant summary: RAD50 c.2750C>T (p.Thr917Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-05 in 232258 control chromosomes. The observed variant frequency is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2750C>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. 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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