Submissions for variant NM_000051.4(ATM):c.2096A>G (p.Glu699Gly)

gnomAD frequency: 0.00077  dbSNP: rs147934285

Total submissions: 16

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: seen in unaffected individuals, 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.
Eurofins Ntd Llc (ga)	RCV000174438	SCV000225742	benign	not specified	2014-12-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204474	SCV000261092	benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	2024-06-28	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, prostate 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, Eygelaar_2022, Gheybi_2023). These reports however, do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28726808, 35039564, 36898365, 23555315, 17333338, 27978560, 27443514, 19781682, 26976419, 25980754, 28135145). ClinVar contains an entry for this variant (Variation ID: 181850). 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
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225458	SCV002505172	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159606	SCV002534077	likely benign	Hereditary cancer-predisposing syndrome	2020-12-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000174438	SCV002760527	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477568	SCV004220068	benign	not provided	2023-08-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589658	SCV005083864	likely benign	Familial cancer of breast	2024-05-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV004551366	SCV000301656	likely benign	ATM-related disorder	2022-03-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.