ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.3206G>T (p.Arg1069Ile) (rs769003601)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219668 SCV000274690 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing The p.R1069I variant (also known as c.3206G>T), located in coding exon 21 of the RAD50 gene, results from a G to T substitution at nucleotide position 3206. The arginine at codon 1069 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well 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 RCV000219668 SCV000753309 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with isoleucine at codon 1069 of the RAD50 protein (p.Arg1069Ile). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant is present in population databases (rs769003601, ExAC 0.02%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 230977). 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 RCV000765808 SCV000897198 uncertain significance Nijmegen breakage syndrome-like disorder 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375528 SCV001572385 uncertain significance not specified 2021-04-01 criteria provided, single submitter clinical testing Variant summary: RAD50 c.3206G>T (p.Arg1069Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 251086 control chromosomes, predominantly at a frequency of 0.0002 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3206G>T in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with another likely pathogenic variant has been reported ( CHEK2 c.349A>G, p.Arg117Gly) in our internal database. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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