ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4049C>T (p.Thr1350Met) (rs587781785)

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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 RCV000130040 SCV000184866 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000589125 SCV000566662 uncertain significance not provided 2019-01-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.4049C>T at the cDNA level, p.Thr1350Met (T1350M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Thr1350Met 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Thr1350Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000543134 SCV000622467 uncertain significance Ataxia-telangiectasia syndrome 2018-12-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1350 of the ATM protein (p.Thr1350Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs587781785, ExAC 0.02%) but has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141486). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000130040 SCV000682180 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589125 SCV000694271 uncertain significance not provided 2017-05-23 criteria provided, single submitter clinical testing Variant summary: The ATM c.4049C>T (p.Thr1350Met) variant involves the alteration of a conserved nucleotide, is located in the Armadillo-type fold of the protein (InterPro) and is predicted to be damaging by 3/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 4/121072 control chromosomes from ExAC at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). In addition, multiple clinical diagnostic laboratories have classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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