ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8261C>T (p.Thr2754Ile) (rs587779871)

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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 RCV000219340 SCV000276084 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000674526 SCV000799876 uncertain significance Ataxia-telangiectasia syndrome 2018-05-11 criteria provided, single submitter clinical testing
GeneDx RCV000115263 SCV000149172 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.8261C>T at the cDNA level, p.Thr2754Ile (T2754I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr2754Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Thr2754Ile occurs at a position that is conserved through mammals and is located within the PI3-PI4 kinase domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Thr2754Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000674526 SCV000944263 uncertain significance Ataxia-telangiectasia syndrome 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2754 of the ATM protein (p.Thr2754Ile). 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 been observed in an individual affected with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 127457). 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: "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.

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