ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8558C>T (p.Thr2853Met) (rs141534716)

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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 RCV000131262 SCV000186227 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000131262 SCV000292153 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing
GeneDx RCV000589725 SCV000209658 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.8558C>T at the cDNA level, p.Thr2853Met (T2853M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been observed in patients with breast cancer, stomach adenocarcinoma, and chronic lymphocytic leukemia (Lu 2015, Nadeu 2016, Decker 2017). ATM Thr2853Met was observed at an allele frequency of 0.01% (3/24,026) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the kinase domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Thr2853Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589725 SCV000694380 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing Variant summary: The ATM c.8558C>T (p.Thr2853Met) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 8/121242 control chromosomes at a frequency of 0.000066, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant has been reported in the literature as a germline and somatic variant in affected patients, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000203831 SCV000260783 uncertain significance Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 2853 of the ATM protein (p.Thr2853Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs141534716, ExAC 0.01%). This variant has been reported in an individual affected with chronic lymphocytic leukemia (PMID: 26837699). ClinVar contains an entry for this variant (Variation ID: 142249). 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 disruptive, but these predictions have not been confirmed by published functional studies. 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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