ClinVar Miner

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

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Total submissions: 11
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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 This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 2020-11-26 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000174438 SCV000301656 likely benign not specified criteria provided, single submitter clinical testing
Color Health, Inc RCV000159606 SCV000687354 likely benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Natera, Inc. RCV000204474 SCV001461088 uncertain significance Ataxia-telangiectasia syndrome 2020-04-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356430 SCV001551595 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Glu699Gly variant was identified in 4 of 9322 proband chromosomes (frequency: 0.0004) from individuals or families with endometrial cancer, breast cancer or Lynch syndrome and was present in 1 of 4490 control chromosomes (frequency: 0.0002) from healthy individuals (Ring 2016, Tavtigian 2009, Tung 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs147934285) as "With other allele", ClinVar (classified as benign by Ambry Genetics and EGL; as likely benign by GeneDx and two other submitters; and as uncertain significance by Invitae, Integrated Genetics/Laboratory Corporation of America and Counsyl). The variant was not identified in LOVD 3.0. The variant was identified in 65 of 276878 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 51 of 24024 chromosomes (freq: 0.002), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 11 of 34400 chromosomes (freq: 0.0003), European in 2 of 126504 chromosomes (freq: 0.00002); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu699 residue is conserved in mammals but not in more distantly related organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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