ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2096A>G (p.Glu699Gly) (rs147934285)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000174438 SCV000209590 likely benign not specified 2017-09-21 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.
Ambry Genetics RCV000159606 SCV000214158 benign Hereditary cancer-predisposing syndrome 2014-12-04 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000174438 SCV000225742 benign not specified 2014-12-29 criteria provided, single submitter clinical testing
Invitae RCV000204474 SCV000261092 likely benign Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000174438 SCV000301656 likely benign not specified criteria provided, single submitter clinical testing
Color RCV000159606 SCV000687354 likely benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000174438 SCV000694208 likely benign not specified 2020-07-30 criteria provided, single submitter clinical testing Variant summary: ATM c.2096A>G (p.Glu699Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251298 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, the variant was also reported in 9 African American individuals in the Flossies database (with a frequency of 0.003517) who were older than 70 years of age, and never had cancer, further suggesting a benign outcome for the variant. c.2096A>G has been reported in the literature in individuals affected with breast Cancer, colorectal cancer, endometrial cancer, pancreatic ductal adenocarcinoma and two individuals being tested for Lynch syndrome (e.g. Yurgelun_2015, Ring_2016, Tung_2016, Yurgelun_2017, Pearlman_2016, Tavtigian_2009, Chaffee_2018). These reports however, 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. Five other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=4) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000204474 SCV000799620 uncertain significance Ataxia-telangiectasia syndrome 2018-04-30 criteria provided, single submitter clinical testing
Mendelics RCV000204474 SCV001138466 likely benign Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing

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