ClinVar Miner

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

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Total submissions: 5
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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 2019-04-05 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000168264 SCV000218935 uncertain significance Ataxia-telangiectasia syndrome 2019-12-05 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.
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.
Color RCV000130241 SCV000911591 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001174859 SCV001338249 uncertain significance not specified 2020-02-07 criteria provided, single submitter clinical testing Variant summary: ATM c.2495G>A (p.Arg832His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 291700 control chromosomes (gnomAD and literature.) This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (4.5e-05 vs 0.001), allowing no conclusion about variant significance. c.2495G>A has been reported in the literature in at least one individual affected with Breast Cancer without strong evidence for causality (Bernstein_2010). The variant has also been detected in healthy controls (e.g. Tiao_2017, Momozawa_2018). A large case-control study found no association for the variant with breast cancer (Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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