ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.3230G>A (p.Arg1077Gln) (rs104895051)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129882 SCV000184699 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-17 criteria provided, single submitter clinical testing The p.R1077Q variant (also known as c.3230G>A), located in coding exon 21 of the RAD50 gene, results from a G to A substitution at nucleotide position 3230. The arginine at codon 1077 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.
Invitae RCV000129882 SCV000548058 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1077 of the RAD50 protein (p.Arg1077Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs104895051, ExAC 0.006%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 127004). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000129882 SCV001251933 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174803 SCV001338149 uncertain significance not specified 2021-02-19 criteria provided, single submitter clinical testing Variant summary: RAD50 c.3230G>A (p.Arg1077Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251224 control chromosomes (gnomAD v2.1 exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3230G>A has been reported in the literature in at least one affected individual found during hereditary-cancer testing, however no disease phenotype was provided (Mu_2016). This report does 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. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Harris Lab, University of Minnesota RCV000114870 SCV000148765 not provided not provided no assertion provided not provided

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