ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.334G>A (p.Ala112Thr) (rs146382972)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115175 SCV000186494 likely benign Hereditary cancer-predisposing syndrome 2018-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting benign classification
Color RCV000115175 SCV000902684 benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000588561 SCV000861417 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515264 SCV000611359 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000588561 SCV000149084 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.334G>A at the cDNA level, p.Ala112Thr (A112T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). Hirsch et al. (2008) did not identify this variant in a series of 31 breast cancer cases of African American ancestry, but did observe it in 1/95 age- and population-matched controls, and Decker et al. (2017) observed this variant in 1/13,087 breast cancer cases and 0/5,488 controls from the United Kingdom. This variant was also observed in a multi-ethnic breast cancer case/control study in which no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). This variant has also been reported in at least two individuals undergoing multi-gene cancer panel testing based on a history of endometrial cancer or a Lynch-syndrome associated cancer and/or polyps (Yurgelun 2015, Ring 2016). ATM Ala112Thr was observed at an allele frequency of 0.27% (66/23,976) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Ala112Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000211948 SCV000593494 uncertain significance not specified 2016-10-07 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000115175 SCV000576457 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588561 SCV000694259 uncertain significance not provided 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The ATM c.334G>A (p.Ala112Thr) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index). This variant was found in 26/116332 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.002473 (24/9706). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant was also reported in breast cancer, Lynch syndrome, and endometrial carcinoma patients, however without strong evidence for pathogenicity. In at least one report, it was found not to have an associated risk with BrC (Haiman_PLOS Genetics_2013). This study concluded that there is no support for the role of protein-coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Multiple clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000195412 SCV000254082 likely benign Ataxia-telangiectasia syndrome 2018-01-09 criteria provided, single submitter clinical testing
Mendelics RCV000195412 SCV000838469 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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