ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.943G>T (p.Val315Leu) (rs28903090)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766671 SCV000149874 uncertain significance not provided 2014-03-11 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.943G>T at the cDNA level, p.Val315Leu (V315L) at the protein level, and results in the change of a Valine to a Leucine (GTA>TTA). This variant has been published in two individuals with familial breast cancer and in two with multiple primaries including laryngeal cancer (Tommiska 2006, Zió Kowska-Suchanek 2013). RAD50 Val315Leu was also reported in one healthy control in Zió Kowska-Suchanek et al (2013). This variant was observed with an allele frequency of 0.3% (23/8600) in European Americans in the NHLBI Exome Sequencing Project, not frequent enough to be considered a polymorphism. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is well conserved throughout evolution and is located in the coiled-coil region per UniProt. In silico analyses predict this variant to have a benign effect on protein structure and function. At 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 RCV000115965 SCV000172788 likely benign Hereditary cancer-predisposing syndrome 2018-12-17 criteria provided, single submitter clinical testing No disease association in small case-control study;Subpopulation frequency in support of benign classification
Invitae RCV000115965 SCV000254909 benign Hereditary cancer-predisposing syndrome 2020-11-26 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212906 SCV000596679 uncertain significance not specified 2016-05-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212906 SCV000920107 benign not specified 2021-03-22 criteria provided, single submitter clinical testing Variant summary: RAD50 c.943G>T (p.Val315Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251062 control chromosomes. The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. c.943G>T has been reported in the literature in individuals affected with a variety of cancers such as breast cancer, multiple primary tumors as well as unaffected control cohorts (example, Harvey_2017, Tommiska_2006, Young_2016, Ziolkowska-Suchanek_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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 (benign, n=1, likely benign, n=1, VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.

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