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

gnomAD frequency: 0.00017  dbSNP: rs370559102

Total submissions: 18

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	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198387	SCV000254141	benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487700	SCV000574908	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	ATM: PM2, BP4
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	likely benign	Ataxia-telangiectasia syndrome	2024-04-09	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	2023-02-08	criteria provided, single submitter	clinical testing	BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798324	SCV002042878	uncertain significance	Breast and/or ovarian cancer	2022-12-21	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	2023-10-23	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487700	SCV004222099	likely benign	not provided	2023-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002291558	SCV005084937	likely benign	Familial cancer of breast	2024-06-13	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].
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.