ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7516A>G (p.Arg2506Gly) (rs200441272)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226242 SCV000283058 uncertain significance Ataxia-telangiectasia syndrome 2018-11-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 2506 of the ATM protein (p.Arg2506Gly). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs200441272, ExAC 0.03%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 236775). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000236767 SCV000292894 uncertain significance not provided 2018-07-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.7516A>G at the cDNA level, p.Arg2506Gly (R2506G) 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 a pathogenic or benign germline variant. ATM Arg2506Gly was observed at an allele frequency of 0.06% (15/23,984) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Arg2506Gly is located in the FAT domain (Stracker 2013). In silico analysis, including protein predictors and evolutionary conservation, supports that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Arg2506Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570854 SCV000660522 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000570854 SCV000903864 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing

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