ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2468G>A (p.Arg823Gln) (rs572533256)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196757 SCV000254887 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 823 of the RAD50 protein (p.Arg823Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs572533256, ExAC 0.05%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 216623). 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.
Ambry Genetics RCV000196757 SCV000663605 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-20 criteria provided, single submitter clinical testing The p.R823Q variant (also known as c.2468G>A), located in coding exon 15 of the RAD50 gene, results from a G to A substitution at nucleotide position 2468. The arginine at codon 823 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781778 SCV000920103 likely benign not specified 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The RAD50 c.2468G>A (p.Arg823Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 21/276876 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.000552 (17/30772). This frequency is about 9 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 South Asian origin. One clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.

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