ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6860G>C (p.Gly2287Ala) (rs1800061)

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Total submissions: 11
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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 In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000168356 SCV000219045 likely benign Ataxia-telangiectasia syndrome 2020-12-07 criteria provided, single submitter clinical testing
Color Health, Inc 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 RCV000588207 SCV000694336 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The ATM c.6860G>C (p.Gly2287Ala) variant involves the alteration of a non-conserved nucleotide and is located within PIK-related kinase, FAT domain of the protein (InterPro) 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 26/121504 control chromosomes including ExAC at a frequency of 0.000214, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant has been reported in multiple HBOC patients without clear evidence supporting causality. 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). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign. Taken together, this variant is classified as VUS-possibly benign.
Counsyl RCV000168356 SCV000797185 uncertain significance Ataxia-telangiectasia syndrome 2018-01-22 criteria provided, single submitter clinical testing
Mendelics RCV000168356 SCV000838583 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 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 Praxis fuer Humangenetik Tuebingen RCV000588207 SCV000892006 uncertain significance not provided 2021-03-01 criteria provided, single submitter clinical testing
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).
Natera, Inc. RCV000168356 SCV001452124 uncertain significance Ataxia-telangiectasia syndrome 2020-01-02 no assertion criteria provided clinical testing

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