ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8732C>T (p.Thr2911Ile) (rs794728018)

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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 RCV000214902 SCV000276312 pathogenic Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbSNP, ESP, 1000 Genomes),in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,Other data supporting pathogenic classification
Color RCV000214902 SCV000905053 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing
GeneDx RCV000486041 SCV000564673 uncertain significance not provided 2015-01-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.8732C>T at the cDNA level, p.Thr2911Ile (T2911I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr2911Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr2911Ile occurs at a position that is moderately conserved across species and is located in PI3K/PI4K domain and the p53 interaction domain (UniProt, Tavtigian 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, it is unclear whether ATM Thr2911Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000537344 SCV000622845 uncertain significance Ataxia-telangiectasia syndrome 2018-04-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2911 of the ATM protein (p.Thr2911Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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: 199662). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Mayo Clinic Health System - Franciscan Health care,Mayo Clinic Health System RCV000181011 SCV000233285 uncertain significance Breast cancer, early-onset 2014-10-09 no assertion criteria provided clinical testing

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