ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5063T>C (p.Ile1688Thr) (rs199836342)

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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 RCV000130648 SCV000185527 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000130648 SCV000687604 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing
GeneDx RCV000484463 SCV000564644 uncertain significance not provided 2018-06-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.5063T>C at the cDNA level, p.Ile1688Thr (I1688T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Ile1688Thr was observed at an allele frequency of 0.09% (15/17246) in individuals of East Asian ancestry 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Ile1688Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000538544 SCV000622562 uncertain significance Ataxia-telangiectasia syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1688 of the ATM protein (p.Ile1688Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs199836342, ExAC 0.2%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141932). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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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