ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3925G>A (p.Ala1309Thr) (rs149711770)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212006 SCV000602552 uncertain significance not specified 2016-08-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115182 SCV000185953 likely benign Hereditary cancer-predisposing syndrome 2017-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768149 SCV000898528 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-06-08 criteria provided, single submitter clinical testing ATM NM_000051.3 exon 26 p.Ala1309Thr (c.3925G>A): This variant has been reported in the literature in 1 individual with breast cancer (Dominguez-Valentin 2018 PMID:29371908). However, this variant is present in 0.1% (156/126510) of European alleles in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:127377) with several conflicting entries between "variant of uncertain significance" and "likely benign". Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain.
Color RCV000115182 SCV000902584 benign Hereditary cancer-predisposing syndrome 2016-03-15 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000122844 SCV000745124 likely benign Ataxia-telangiectasia syndrome 2014-12-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587234 SCV000228296 uncertain significance not provided 2014-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000212006 SCV000149091 likely benign not specified 2017-12-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago RCV000212006 SCV000593510 uncertain significance not specified 2017-03-08 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000122844 SCV000745812 likely benign Ataxia-telangiectasia syndrome 2016-11-14 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587234 SCV000694267 likely benign not provided 2016-05-20 criteria provided, single submitter clinical testing Variant summary: The ATM c.3925G>A (p.Ala1309Thr) variant causes a missense change involving a conserved nucleotide with 2/3 in silico tools (SNPs&GO and MutationTaster not captured here due to low reliability index and p-value) predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 75/121298 (1/1617, frequency: 0.0006183), predominantly in the European (Non-Finnish) cohort, 61/66688 (1/1093, frequency: 0.0009147), which exceeds the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/2000 (0.0005001) for Breast Cancer. Therefore, suggesting this variant is a common polymorphism found in population(s) of European (Non-Finnish) origin. The variant of interest has been reported in multiple affected individuals dx with predominantly breast cancer but also pts dx with Lynch syndrome, however without strong evidence for causality. It has also been reported in patients with lymphoma and lung adenocarcinoma with unconfirmed somatic status. In a large meta-analysis case-control study, the variant was no associated with an increased risk for breast cancer. Multiple reputable clinical laboratories cite the variant with conflicting classifications and phenotypes: "Uncertain significance - Hereditary cancer," , "Uncertain significance - Ataxia-telangiectasia," and "likely benign - Hereditary Cancer." Taken together, it has been classified as Likely Benign.
Invitae RCV000122844 SCV000166102 likely benign Ataxia-telangiectasia syndrome 2017-12-28 criteria provided, single submitter clinical testing
Mendelics RCV000122844 SCV000838528 likely benign Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000587234 SCV000805543 likely benign not provided 2017-07-06 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115182 SCV000787861 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 no assertion criteria provided clinical testing

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