ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1378A>C (p.Thr460Pro) (rs587782729)

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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 RCV000132224 SCV000187306 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000132224 SCV000913544 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000483286 SCV000567592 uncertain significance not provided 2015-08-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.1378A>C at the cDNA level, p.Thr460Pro (T460P) at the protein level, and results in the change of a Threonine to a Proline (ACG>CCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr460Pro 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 Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr460Pro occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Thr460Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000471709 SCV000546795 uncertain significance Ataxia-telangiectasia syndrome 2018-08-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 460 of the ATM protein (p.Thr460Pro). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142803). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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