ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6313A>G (p.Arg2105Gly) (rs879253983)

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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 RCV000570295 SCV000660782 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
GeneDx RCV000236852 SCV000293063 uncertain significance not provided 2016-02-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.6313A>G at the cDNA level, p.Arg2105Gly (R2105G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg2105Gly 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 Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg2105Gly occurs at a position that is conserved across species and is located in the FAT domain (Tavtigian 2009, Stracker 2013). 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 Arg2105Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000471131 SCV000546944 uncertain significance Ataxia-telangiectasia syndrome 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 2105 of the ATM protein (p.Arg2105Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine 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 ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 245884). 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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