ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2047G>A (p.Val683Ile) (rs367925756)

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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 RCV000164991 SCV000215685 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-26 criteria provided, single submitter clinical testing The p.V683I variant (also known as c.2047G>A), located in coding exon 13 of the RAD50 gene, results from a G to A substitution at nucleotide position 2047. The valine at codon 683 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported in 1/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). It was also reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet. 2016 Jun;53:366-76). This amino acid position is highly 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 RCV000164991 SCV000262064 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 683 of the RAD50 protein (p.Val683Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs367925756, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 24894818). ClinVar contains an entry for this variant (Variation ID: 185548). 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.
Fulgent Genetics,Fulgent Genetics RCV000764583 SCV000895674 uncertain significance Nijmegen breakage syndrome-like disorder 2018-10-31 criteria provided, single submitter clinical testing

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