ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3467C>T (p.Thr1156Met) (rs759951393)

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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 RCV000162792 SCV000213270 likely benign Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient evidence,Other strong data supporting benign classification
Color RCV000162792 SCV000911161 likely benign Hereditary cancer-predisposing syndrome 2016-03-03 criteria provided, single submitter clinical testing
GeneDx RCV000478106 SCV000566875 uncertain significance not provided 2017-04-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.3467C>T at the cDNA level, p.Thr1156Met (T1156M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant was observed in 1/2,531 cases and absent in 2,245 controls in a breast cancer case-control meta-analysis, and was also identified in an individual with breast cancer undergoing multigene hereditary cancer panel testing (Tavtigian 2009, Tung 2016). ATM Thr1156Met was not observed at a significant allele frequency 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 Thr1156Met occurs at a position that is not conserved and is located within the beta-adaptin interaction 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 Thr1156Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000167875 SCV000218521 uncertain significance Ataxia-telangiectasia syndrome 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1156 of the ATM protein (p.Thr1156Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs759951393, ExAC <0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 19781682, 26976419). ClinVar contains an entry for this variant (Variation ID: 183918). 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 also 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. 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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