ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115941 SCV000186667 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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.
Invitae RCV000115941 SCV000254889 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 842 of the RAD50 protein (p.Val842Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs28903093, ExAC 0.04%). This variant has been reported in individuals affected with breast cancer. Currently, there is insufficient evidence to conclude whether or not this variant segregates with disease (PMID: 24894818, 16385572). ClinVar contains an entry for this variant (Variation ID: 128005). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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