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 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 2019-12-01 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%). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 141486). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000130040 SCV000682180 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001255215 SCV000694271 uncertain significance not specified 2020-08-20 criteria provided, single submitter clinical testing Variant summary: ATM c.4049C>T (p.Thr1350Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 271256 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (5.2e-05 vs 0.004), allowing no conclusion about variant significance. c.4049C>T has been reported in the literature in at least one individual affected with familial cutaneous melanoma (e.g. Pastorino_2020) and in at least one healthy control subject (e.g. Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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