ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7370A>C (p.Glu2457Ala) (rs778482902)

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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 RCV000218733 SCV000275191 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000218733 SCV000687768 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-28 criteria provided, single submitter clinical testing
GeneDx RCV000485580 SCV000571025 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.7370A>C at the cDNA level, p.Glu2457Ala (E2457A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Glu2457Ala 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 Glu2457Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000701716 SCV000830529 uncertain significance Ataxia-telangiectasia syndrome 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 2457 of the ATM protein (p.Glu2457Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs778482902, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 231363). 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. 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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