ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.184A>G (p.Arg62Gly) (rs876659407)

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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 RCV000223254 SCV000275836 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000464631 SCV000546969 uncertain significance Ataxia-telangiectasia syndrome 2016-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 62 of the ATM protein (p.Arg62Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 231859). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on mRNA splicing and protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000479547 SCV000570027 uncertain significance not provided 2016-04-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.184A>G at the cDNA level, p.Arg62Gly (R62G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg62Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Arg62Gly occurs at a position that is conserved in mammals and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). Protein based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. In addition, in silico splicing models are uninformative. Based on currently available evidence, it is unclear whether ATM Arg62Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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