ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8138G>C (p.Arg2713Thr) (rs876659351)

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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 RCV000567578 SCV000667812 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000522072 SCV000616648 uncertain significance not provided 2018-08-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.8138G>C at the cDNA level, p.Arg2713Thr (R2713T) at the protein level, and results in the change of an Arginine to a Threonine (AGA>ACA) in exon 55. This variant has not, to our knowledge, been published in the literature as either a mutation or a benign polymorphism. ATM Arg2713Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Arg2713Thr alters a position that is conserved across species, with Threonine being the naturally occurring amino acid at this position in one species, and is located in the PI3K/PI4K domain (Tavtigian 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Arg2713Thr is a pathogenic or a benign variant
Invitae RCV000819092 SCV000959735 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 2713 of the ATM protein (p.Arg2713Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 448987). 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 disruptive, 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.

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