ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2495G>A (p.Arg832His) (rs199875915)

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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 RCV000130241 SCV000185084 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000130241 SCV000911591 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000483469 SCV000571820 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.2495G>A at the cDNA level, p.Arg832His (R832H) 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 pathogenic or benign. ATM Arg832His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. ATM Arg832His is not located in a known functional domain. 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 Arg832His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168264 SCV000218935 uncertain significance Ataxia-telangiectasia syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 832 of the ATM protein (p.Arg832His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199875915, ExAC 0.006%). This variant has been observed in an individual affected with gastric adenocarcinoma, and without a known diagnosis of ataxia-telangiectasia (Invitae database). However, in that individual, a pathogenic allele was also identified in ATM, which suggests that this c.2495G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 141644). 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. 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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