ClinVar Miner

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

gnomAD frequency: 0.00096  dbSNP: rs1800061
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Total submissions: 18
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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: 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.
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 2024-02-22 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 0.00019 in 251446 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00019 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. c.6860G>C has been reported in the literature in individuals affected with Breast Cancer or Pancreatic Cancer (Dork_2001, Navrkalova_2013, Caminsky_2016, Tung_2016, Yurgelun_2017, Dorling_2021, Yu_2022) without strong evidence of causality, and was also found in unaffected controls. These reports 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 the variant allele indicating a benign outcome (Vorechovsky_1996). The following publications have been ascertained in the context of this evaluation (PMID: 11606401, 19781682, 23585524, 11805335, 26898890, 26976419, 8665503, 28135145, 30374176, 31920950, 33471991, 35047863). ClinVar contains an entry for this variant (Variation ID: 127428). 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 2024-04-01 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; 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 RCV004549565 SCV004745280 likely benign ATM-related disorder 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).
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000115233 SCV005045487 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000168356 SCV001452124 uncertain significance Ataxia-telangiectasia syndrome 2020-01-02 no assertion criteria provided clinical testing

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