ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs367925756
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Total submissions: 7
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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 2022-12-16 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000164991 SCV000262064 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-06 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 683 of the RAD50 protein (p.Val683Ile). This variant is present in population databases (rs367925756, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 24894818). ClinVar contains an entry for this variant (Variation ID: 185548). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD50 protein function with a negative predictive value of 80%. 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
Sema4, Sema4 RCV000764583 SCV002538466 uncertain significance Nijmegen breakage syndrome-like disorder 2021-11-05 criteria provided, single submitter curation
Baylor Genetics RCV000764583 SCV005052639 uncertain significance Nijmegen breakage syndrome-like disorder 2024-01-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV004998328 SCV005625130 uncertain significance not provided 2024-05-09 criteria provided, single submitter clinical testing The RAD50 c.2047G>A (p.Val683Ile) variant has been reported in the published literature in an early onset breast cancer (PMID: 24894818 (2014)), as well as in breast cancer cases and reportedly healthy individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD50)). The frequency of this variant in the general population, 0.00035 (4/11496 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Salgia Laboratory, City of Hope RCV003322600 SCV003804200 uncertain significance Lung sarcomatoid carcinoma no assertion criteria provided clinical testing

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