ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4196C>G (p.Thr1399Ser) (rs786203761)

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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 RCV000215942 SCV000276255 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000215942 SCV000682189 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000486909 SCV000564639 uncertain significance not provided 2018-10-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.4196C>G at the cDNA level, p.Thr1399Ser (T1399S) at the protein level, and results in the change of a Threonine to a Serine (ACC>AGC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Thr1399Ser was not observed in large population cohorts (Lek 2016). This variant is not located within 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 Thr1399Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473821 SCV000546704 uncertain significance Ataxia-telangiectasia syndrome 2018-02-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 1399 of the ATM protein (p.Thr1399Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. 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: 232191). 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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