ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7778A>G (p.Gln2593Arg) (rs587779867)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588147 SCV000149164 uncertain significance not provided 2018-11-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.7778A>G at the cDNA level, p.Gln2593Arg (Q2593R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant was observed in at least two individuals with a personal history of early-onset breast cancer (Maxwell 2014, Rummel 2017). This variant was also identified in an additional individual with breast cancer and was absent from a control population (Decker 2017). ATM Gln2593Arg was observed at an allele frequency of 0.16% (16/10124) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). ATM Gln2593Arg 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 Gln2593Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115255 SCV000185534 likely benign Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;No disease association in small case-control study
Invitae RCV000197623 SCV000254149 likely benign Ataxia-telangiectasia syndrome 2020-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115255 SCV000537522 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces glutamine with arginine at codon 2593 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25503501, 28503720, 28779002). This variant has also been identified in 21/250896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588147 SCV000694359 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The ATM c.7778A>G (p.Gln2593Arg) variant involves the alteration of a non-conserved nucleotide, which is not located in any known domain. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). This variant was found in 7/120322 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000106 (7/66092). The allele frequency of this variant in a cohort of European American women who are cancer free and older than age 70 is 0.000273 (2/7325, Flossies database), which is higher than the frequency in ExAC European (Non-Finnish) subpopulation, suggesting this variant is a benign polymorphism. In addition, multiple clinical diagnostics laboratories classified this variant as VUS, however, one publication classified this variant as likely benign. Taken together, this variant is classified as VUS-possibly benign.
Counsyl RCV000197623 SCV000799961 uncertain significance Ataxia-telangiectasia syndrome 2018-05-14 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001257470 SCV001434276 uncertain significance Familial cancer of breast 2019-10-04 criteria provided, single submitter clinical testing This variant has been reported in the literature in several individuals with breast cancer (Maxwell 2015, Rummel 2017, Decker 2017). This variant has an overall allele frequency of 0.00008 in the Broad Institute gnomAD Browser ( In silico analyses indicate this is an evolutionarily conserved residue. PP3
Natera, Inc. RCV000197623 SCV001462593 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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