ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1838T>G (p.Val613Gly) (rs762018538)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472274 SCV000547076 uncertain significance Ataxia-telangiectasia syndrome 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 613 of the ATM protein (p.Val613Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 407687). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000572810 SCV000660488 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-20 criteria provided, single submitter clinical testing Insufficient evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign)
Color RCV000572810 SCV000682005 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194266 SCV001363658 uncertain significance not specified 2019-03-26 criteria provided, single submitter clinical testing Variant summary: ATM c.1838T>G (p.Val613Gly) 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 was absent in 245726 control chromosomes (gnomAD). 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.1838T>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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