ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7187C>G (p.Thr2396Ser)

gnomAD frequency: 0.00017  dbSNP: rs370559102
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487700 SCV000149152 likely benign not provided 2021-02-04 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9288106, 19781682, 29036293, 11054065, 25980754, 22529920, 19404735, 18384426, 21787400, 20826828, 10026998, 26787654, 28779002, 27443514, 20305132, 25186627, 28135145, 31159747, 29522266)
Ambry Genetics RCV000115243 SCV000172917 likely benign Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Other data supporting benign classification
Invitae RCV000198387 SCV000254141 benign Ataxia-telangiectasia syndrome 2021-12-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000487700 SCV000574908 uncertain significance not provided 2019-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855569 SCV000694347 benign not specified 2021-07-03 criteria provided, single submitter clinical testing Variant summary: ATM c.7187C>G (p.Thr2396Ser) results in a conservative amino acid change located in the FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 256616 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00021 vs 0.001), allowing no conclusion about variant significance. In addition, the variant was also reported in 3/7325 European American women (i.e. with a frequency of 0.00041), who were older than 70 years of age, and never had cancer (in the FLOSSIES database). c.7187C>G has been reported in the literature as a VUS in settings of multigene cancer panel testing in individuals affected with a variety of cancers (example, breast, ovarian, melanoma, CLL, Lynch syndrome) with limited information (e.g. Paglia 2010, Tung_2015, Tavera-Tapia 2017, Goldstein 2017, Tiao 2017, Hauke 2018, Bonache_2018, Tsaousis_2019, Ferrer-Avargues_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature as we all as observed at our laboratory (our lab, BRCA1 c.3400G>T, p.Glu1134* ; Ferrer-Avargues_2021, MSH6 c.2079dup, p.Cys694MetfsTer), providing supporting evidence for a benign role. To our knowledge, no concrete experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; likely benign, n=2, VUS, n=7). At-least one of these submitters has re-classified this variant to likely benign since its previous evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
GeneKor MSA RCV000115243 SCV000821868 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000198387 SCV000838589 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000487700 SCV000861290 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115243 SCV000910619 likely benign Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000198387 SCV001261058 uncertain significance Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories,Mayo Clinic RCV000487700 SCV001713584 uncertain significance not provided 2019-09-08 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798324 SCV002042878 uncertain significance Breast and/or ovarian cancer 2020-03-25 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000855569 SCV002072082 uncertain significance not specified 2021-06-01 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000115243 SCV002537019 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-01 criteria provided, single submitter curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002291558 SCV002584562 uncertain significance Familial cancer of breast 2022-08-17 criteria provided, single submitter clinical testing The ATM c.7187C>G (p.Thr2396Ser) missense change has a maximum subpopulation frequency of 0.045% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer and/or ovarian cancer (PMID: 18384426, 19404735, 25186627, 30306255, 31159747). This variant has been reported in 3 individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/) and in 4 of 1358 control individuals collected as part of a non-cancer studies (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
GenomeConnect, ClinGen RCV000487700 SCV002074895 not provided not provided no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 07-22-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.