ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5953A>G (p.Thr1985Ala) (rs879254252)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236411 SCV000293967 uncertain significance not provided 2017-12-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.5953A>G at the cDNA level, p.Thr1985Ala (T1985A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has been reported in at least one individual with breast cancer (Decker 2017). Functional studies interrogating ATM Thr1985Ala on its own or in combination with variants at neighboring residues found no impact on phosphorylation or kinase activity (Yamaguchi 2007, Zhou 2017). ATM Thr1985Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Thr1985Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000823004 SCV000963838 uncertain significance Ataxia-telangiectasia syndrome 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1985 of the ATM protein (p.Thr1985Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. 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: 246420). 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 alanine 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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