ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2699T>C (p.Met900Thr) (rs863224558)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199775 SCV000254073 uncertain significance Ataxia-telangiectasia syndrome 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 900 of the ATM protein (p.Met900Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 216196). 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 and their clinical significance is uncertain. 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.
GeneDx RCV000484957 SCV000566433 uncertain significance not provided 2015-04-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.2699T>C at the cDNA level, p.Met900Thr (M900T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Met900Thr 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 Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Met900Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is not located in a known functional domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Met900Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563645 SCV000665447 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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