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
Ambry Genetics RCV000115965 SCV000172788 likely benign Hereditary cancer-predisposing syndrome 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,No disease association in small case-control study
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.
Genetic Services Laboratory, University of Chicago RCV000212906 SCV000596679 uncertain significance not specified 2016-05-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212906 SCV000920107 likely benign not specified 2018-01-08 criteria provided, single submitter clinical testing Variant summary: The RAD50 c.943G>T (p.Val315Leu) variant involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a damaging outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 334/276754 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.002047 (257/125536). This frequency is about 33 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple publications have cited the variant in affected individuals with limited information (ie, lack of co-occurrence and/or cosegregation data). In addition, multiple clinical diagnostic laboratories cite the variant with conflicting classifications, "uncertain significance" or "likely benign." Taken together, this variant is classified as likely benign.
Invitae RCV000115965 SCV000254909 likely benign Hereditary cancer-predisposing syndrome 2018-01-09 criteria provided, single submitter clinical testing

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