ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2525T>C (p.Val842Ala) (rs28903093)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212917 SCV000149850 uncertain significance not provided 2014-02-19 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.2525T>C at the cDNA level, p.Val842Ala (V842A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant was observed in an individual with breast cancer and a family history of breast cancer (Tommiska 2006). RAD50 Val842Ala was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is well conserved through mammals and is located in a potential coil-coiled region (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 RCV000115941 SCV000186667 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing The p.V842A variant (also known as c.2525T>C), located in coding exon 16 of the RAD50 gene, results from a T to C substitution at nucleotide position 2525. The valine at codon 842 is replaced by alanine, an amino acid with similar properties. This change occurs at the first nucleotide of coding exon 16. This variant has been detected in a familial breast cancer kindred from the United Kingdom; however, specific clinical information and co-segregation data is not available (Tommiska J et al. Int. J. Cancer. 2006 Jun;118:2911-6). This amino acid position is 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 RCV000115941 SCV000254889 likely benign Hereditary cancer-predisposing syndrome 2020-12-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264454 SCV001442620 likely benign not specified 2020-10-05 criteria provided, single submitter clinical testing Variant summary: RAD50 c.2525T>C (p.Val842Ala) results in a non-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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 279768 control chromosomes, predominantly at a frequency of 0.0002 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.2 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2525T>C has been reported in the literature in individuals affected with breast cancer or non-Hodgkin lymphoma (Tommiska_2006, Schuetz_2009, Damiola_2014). These reports 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. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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