ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7358G>A (p.Arg2453His) (rs587781361)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129153 SCV000183876 likely benign Hereditary cancer-predisposing syndrome 2017-11-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000129153 SCV000903239 likely benign Hereditary cancer-predisposing syndrome 2015-12-14 criteria provided, single submitter clinical testing
GeneDx RCV000212065 SCV000209642 uncertain significance not provided 2017-10-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.7358G>A at the cDNA level, p.Arg2453His (R2453H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as germline variant; however, it has been reported as a somatic variant in Ewing sarcoma samples (Crompton 2014). ATM Arg2453His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Arg2453His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233904 SCV000283049 uncertain significance Ataxia-telangiectasia syndrome 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2453 of the ATM protein (p.Arg2453His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587781361, ExAC 0.006%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 140905). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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