ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1287A>G (p.Ile429Met) (rs1554098314)

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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 RCV000560978 SCV000671781 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-02 criteria provided, single submitter clinical testing The p.I429M variant (also known as c.1287A>G), located in coding exon 9 of the RAD50 gene, results from an A to G substitution at nucleotide position 1287. The isoleucine at codon 429 is replaced by methionine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000alleles tested) in our clinical cohort.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 RCV000560978 SCV000753306 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 429 of the RAD50 protein (p.Ile429Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 484649). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264575 SCV001442798 uncertain significance not specified 2020-10-09 criteria provided, single submitter clinical testing Variant summary: RAD50 c.1287A>G (p.Ile429Met) results in a 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 was absent in 248772 control chromosomes. 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.1287A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two 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.

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