ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3016A>G (p.Met1006Val) (rs139893395)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131127 SCV000186059 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585220 SCV000692732 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing
Color RCV000131127 SCV000902981 likely benign Hereditary cancer-predisposing syndrome 2016-04-27 criteria provided, single submitter clinical testing
GeneDx RCV000585220 SCV000278818 uncertain significance not provided 2018-10-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.3016A>G at the cDNA level, p.Met1006Val (M1006V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been reported in at least one individual with breast cancer, in another individual referred for hereditary cancer testing, and in healthy control subjects (Mauer 2014, Decker 2017, Tiao 2017). ATM Met1006Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with beta-adaptin (Tavtigian 2009). 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 Met1006Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000131127 SCV000821845 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000205686 SCV000260899 uncertain significance Ataxia-telangiectasia syndrome 2018-12-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1006 of the ATM protein (p.Met1006Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs139893395, ExAC 0.009%). This variant has been reported in an individual with a personal history of cancer (PMID: 24113346). ClinVar contains an entry for this variant (Variation ID: 142162). 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 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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