ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5639C>T (p.Thr1880Met) (rs587780628)

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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 RCV000131551 SCV000186551 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000131551 SCV000682276 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing
GeneDx RCV000212030 SCV000209788 uncertain significance not provided 2017-06-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.5639C>T at the cDNA level, p.Thr1880Met (T1880M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr1880Met was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr1880Met occurs at a position that is not conserved and is not located in a known functional domain. 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 Thr1880Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122860 SCV000166118 uncertain significance Ataxia-telangiectasia syndrome 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1880 of the ATM protein (p.Thr1880Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. 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: 135761). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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