ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1661C>T (p.Thr554Met) (rs1060501694)

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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 RCV000561104 SCV000667868 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000561104 SCV000681991 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000484925 SCV000567369 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.1661C>T at the cDNA level, p.Thr554Met (T554M) 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 Thr554Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr554Met occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). 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 Thr554Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000458148 SCV000547111 uncertain significance Ataxia-telangiectasia syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 554 of the ATM protein (p.Thr554Met). 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: 407709). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; 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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