Submissions for variant NM_000051.4(ATM):c.6860G>C (p.Gly2287Ala)

gnomAD frequency: 0.00096  dbSNP: rs1800061

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588207	SCV000149142	likely benign	not provided	2020-11-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 8665503, 26976419, 11606401, 23585524, 19781682, 22529920, 11805335, 25980754, 28135145, 16652348, 15159313, 15279808, 10464642, 30374176, 26206375, 26898890, 29300386, 30197789)
Ambry Genetics	RCV000115233	SCV000185781	likely benign	Hereditary cancer-predisposing syndrome	2018-10-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Invitae	RCV000168356	SCV000219045	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115233	SCV000537435	likely benign	Hereditary cancer-predisposing syndrome	2015-03-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281932	SCV000694336	likely benign	not specified	2022-07-11	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6860G>C (p.Gly2287Ala) results in a non-conservative amino acid change located in the FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 282830 control chromosomes, predominantly at a frequency of 0.00051 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00028 vs 0.001), allowing no conclusion about variant significance. In addition, this variant has also been reported in 4 European American individuals in Flossies database. This cohort consists of individuals older than age 70 years who never had cancer. The variant, c.6860G>C has been reported in the literature in individuals affected with Breast Cancer (Dork_2001, Navrkalova_2013, Caminsky_2016, Tung_2016, Yurgelun_2017) without strong evidence of causality. These reports therefore, do not provide unequivocal conclusions about association of the variant with Breast Cancer. A comprehensive functional study showed that this variant does not affect ATM function (Scott_PNAS_2002). In addition, tumor analysis of one breast cancer patient showed loss of variant allele indicating benign outcome (Vorechovsky_1996). Thirteen other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=7) or uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000168356	SCV000797185	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000168356	SCV000838583	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000757936	SCV000886465	likely benign	Familial cancer of breast	2018-05-17	criteria provided, single submitter	research	The ATM variant designated as NM_000051.3: c.6860G>C (p.Gly2287Ala) is classified as likely benign. This variant has been reported in several population databases. It is present in approximately 1 in 2000 individuals with European ancestry. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 127428). Computer software programs predict that this variant will be tolerated (Polyphen-2, SIFT). An in vitro study has shown that this variant does not affect protein function (Scott et al, 2002, PMID:11805335). Together, this information is consistent with a likely benign variant in ATM. Bayesian analysis integrating data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter ATM function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
CeGaT Center for Human Genetics Tuebingen	RCV000588207	SCV000892006	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ATM: BP4
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000115233	SCV001911479	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.6860G>C (p.Gly2287Ala) variant has an allele frequency of 0.00025 (0.03%, 69/268,070 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00050 (0.05%, 59/117,970 alleles) in the European (non-Finnish) subpopulation. However, the 99% confidence interval for this frequency is 0.036%, lower than the 0.05% cut-off for BS1 criterion (no population frequency criterion met; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BP4 (PMID: 33280026).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000588207	SCV002010789	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798322	SCV002042800	uncertain significance	Breast and/or ovarian cancer	2022-05-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115233	SCV002538516	likely benign	Hereditary cancer-predisposing syndrome	2021-01-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002281932	SCV002760689	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002281932	SCV002774012	benign	not specified	2022-03-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925110	SCV004745280	likely benign	ATM-related condition	2023-09-06	criteria provided, single submitter	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.	RCV000168356	SCV001452124	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-02	no assertion criteria provided	clinical testing