ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1726A>G (p.Ile576Val) (rs1064795170)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000582520 SCV000687322 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000486868 SCV000570699 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.1726A>G at the cDNA level, p.Ile576Val (I576V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant was observed in the tumor sample from a pediatric patient with an intracranial myxoid mesenchymal neoplasm, who had a history of adrenal neuroblastoma (Bale 2017). ATM Ile576Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 Ile576Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000690771 SCV000818497 uncertain significance Ataxia-telangiectasia syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 576 of the ATM protein (p.Ile576Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 421483). 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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