ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2606C>T (p.Ala869Val) (rs145513717)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166230 SCV000217009 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166230 SCV000911327 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000225924 SCV000789211 uncertain significance Ataxia-telangiectasia syndrome 2017-01-24 criteria provided, single submitter clinical testing
GeneDx RCV000487118 SCV000564619 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing This variant is denoted ATM c.2606C>T at the cDNA level, p.Ala869Val (A869V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant was observed in 1/13,087 breast cancer cases and in 1/5,488 controls (Decker 2017). ATM Ala869Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analyses 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 Ala869Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000225924 SCV000282906 uncertain significance Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 869 of the ATM protein (p.Ala869Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs145513717, ExAC 0.001%) but has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186608). 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 valine 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, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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