ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8260A>G (p.Thr2754Ala) (rs587781414)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129278 SCV000184038 uncertain significance Hereditary cancer-predisposing syndrome 2013-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000489256 SCV000577628 uncertain significance not provided 2015-12-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.8260A>G at the cDNA level, p.Thr2754Ala (T2754A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr2754Ala 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 Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr2754Ala occurs at a position that is conserved in mammals and is located in the PI3K/PI4K domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Thr2754Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000467996 SCV000547121 uncertain significance Ataxia-telangiectasia syndrome 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 2754 of the ATM protein (p.Thr2754Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. 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: 140982). 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 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.

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