ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.9031A>G (p.Met3011Val) (rs372795527)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212097 SCV000885033 uncertain significance not provided 2017-10-11 criteria provided, single submitter clinical testing The p.Met3011Val (rs372795527) has been reported in several individuals with breast carcinoma or a family history of breast cancer (Tavtigian, 2009; Teraoka, 2001; Thorstenson, 2003); however this variant has not been found associated with ataxia-telangiectasia nor primary immunodeficiency. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.004 percent (identified on 11 out of 277,168 chromosomes), and has been reported to the ClinVar database as a variant of unknown significance (VariationID: 181906). The methionine at position 3,011 is moderately conserved considering 9 species (Alamut v2.10) and computational analyses of the p.Met3011Val variant on protein structure and function indicate a neutral effect (SIFT: tolerated, GVGD: class C0, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Met3011Val variant with certainty.
Ambry Genetics RCV000159670 SCV000215431 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000159670 SCV000682535 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000212097 SCV000209671 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing This variant is denoted ATM c.9031A>G at the cDNA level, p.Met3011Val (M3011V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been observed in several individuals with either a personal or family history of breast cancer and in an individual with glioblastoma, but was also identified in at least one control subject (Teraoka 2001, Thorsteson 2003, Tavtigian 2009, Lu 2015, Pritchard 2018). ATM Met3011Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FATC 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 Met3011Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779780 SCV000916570 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: ATM c.9031A>G (p.Met3011Val) results in a conservative amino acid change located in the catalytic domain of the Phosphatidylinositol 3-/4-kinase of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant was observed with an allele frequency of 3.9e-05 in 281966 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (3.9e-05 vs 1.00e-03), allowing no conclusion about variant significance. The variant, c.9031A>G, has been reported in the literature in individuals affected with Breast Cancer (Tavtigian_2009, Teraoka_2001, Thorstenson_2003) along with multiple somatic occurrences that were not specified to be germline assessed (Aleksic_2016, Siroy_2015, Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000196967 SCV000254160 uncertain significance Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 3011 of the ATM protein (p.Met3011Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs372795527, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer and glioblastoma multiforme (PMID: 11505391, 12810666, 19781682, 26689913). ClinVar contains an entry for this variant (Variation ID: 181906). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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