ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131127 SCV000186059 likely benign Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Invitae RCV000205686 SCV000260899 uncertain significance Ataxia-telangiectasia syndrome 2019-12-27 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 observed 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.
GeneDx RCV000585220 SCV000278818 uncertain significance not provided 2020-04-27 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Decker 2017); This variant is associated with the following publications: (PMID: 28779002, 28652578, 24113346, 31159747)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585220 SCV000692732 uncertain significance not provided 2017-07-01 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131127 SCV000821845 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131127 SCV000902981 likely benign Hereditary cancer-predisposing syndrome 2016-04-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001328457 SCV001519598 uncertain significance not specified 2021-03-08 criteria provided, single submitter clinical testing Variant summary: ATM c.3016A>G (p.Met1006Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251338 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.8e-05 vs 0.004), allowing no conclusion about variant significance. c.3016A>G has been reported in the literature as a VUS in individuals undergoing multigene cancer panel testing as well as in unaffected control cohorts (example, Mauer_2014, Tsaousis_2019, Tiao_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia and/or breast cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.

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