Submissions for variant NM_000051.4(ATM):c.6067G>A (p.Gly2023Arg)

gnomAD frequency: 0.00124  dbSNP: rs11212587

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513642	SCV000149130	likely benign	not provided	2021-06-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26976419, 26787654, 26094658, 27153395, 21933854, 29445900, 26053404, 19404735, 11505391, 17393301, 12810666, 22529920, 23091097, 17968022, 12149228, 16461462, 21787400, 19781682, 24728327, 25624042, 26898890, 27664052, 25980754, 24584352, 27150160, 26483394, 26822149, 27882345, 25625042, 27498913, 28608266, 29678143, 23555315, 26822949, 27621404, 28779002, 30197789, 31108397, 30309722, 31159747, 30303537, 32854451)
Invitae	RCV000122864	SCV000166122	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115221	SCV000183877	likely benign	Hereditary cancer-predisposing syndrome	2018-07-27	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.
PreventionGenetics, part of Exact Sciences	RCV000120151	SCV000301678	benign	not specified		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513642	SCV000608617	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ATM: BS1:Supporting
Color Diagnostics, LLC DBA Color Health	RCV000115221	SCV000687670	likely benign	Hereditary cancer-predisposing syndrome	2015-02-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000513642	SCV000694314	benign	not provided	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.6067G>A (p.Gly2023Arg) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 397/277154 (1 homozygote) control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.002368 (300/126680). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple publications have cited the variant in affected BrC pts, along with multiple somatic occurrences in MCL and CLL pts. Skowronska_2012 suggestions, biallelic ATM inactivation in CLL patients was associated with disease progression and reduced survival. However, the variant has been reported to co-occur with a BRCA1 variant, although the exact variant was not indicated (Thorstenson_2003). In addition, two internal LCA samples report the variant to co-occur with a pathogenic ATM variant, c.6095G>A (p.Arg20232Lys) and BRCA1 variant, c.1326T>A (p.Cys442X). In addition, multiple clinical diagnostic laboratories cite the variant as "likely benign/benign." Taken together, this variant is classified as benign.
GeneKor MSA	RCV000115221	SCV000821865	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000122864	SCV000838565	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000513642	SCV000840948	likely benign	not provided	2019-12-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000122864	SCV001263992	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253480	SCV001429203	uncertain significance	Familial cancer of breast	2018-12-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000513642	SCV001469357	likely benign	not provided	2023-04-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000513642	SCV001713581	uncertain significance	not provided	2023-02-17	criteria provided, single submitter	clinical testing	BS1
Genome-Nilou Lab	RCV000122864	SCV001781325	likely benign	Ataxia-telangiectasia syndrome	2021-07-14	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000115221	SCV001911470	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.6067G>A (p.Gly2023Arg) variant has an allele frequency of 0.0014 (0.14%, 374/268,256 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0023 (0.232%, 274/118,126 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant 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, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). 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: BS1 + PP3 (PMID: 33280026).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000513642	SCV002010799	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798320	SCV002042698	likely benign	Breast and/or ovarian cancer	2023-03-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120151	SCV002070957	likely benign	not specified	2021-12-30	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225321	SCV002504743	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115221	SCV002537561	benign	Hereditary cancer-predisposing syndrome	2020-07-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120151	SCV002760723	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513642	SCV003800554	likely benign	not provided	2022-10-20	criteria provided, single submitter	clinical testing
ITMI	RCV000120151	SCV000084292	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000115221	SCV000805219	uncertain significance	Hereditary cancer-predisposing syndrome	2018-03-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000122864	SCV001452119	likely benign	Ataxia-telangiectasia syndrome	2020-04-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356569	SCV001551777	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Gly2023Arg variant was identified in 15 of 8674 proband chromosomes (frequency: 0.002) from individuals or families with CLL, lymphoid neoplasms, colorectal or breast cancer and was identified in 2 of 1602 chromosomes (frequency: 0.001) from healthy individuals (Broeks 2008, Gronbaek 2002, Mangone 2015, Paglia 2010, Podralska 2018, Skowronska 2012, Thorstenson 2003, Yurgelun 2015, Balmana 2016, Tung 2016). The variant was also identified in dbSNP (ID: rs11212587) as "With other allele", ClinVar (classified as benign by two clinical laboratories; as likely benign by Invitae, Ambry Genetics and three other submitters; as uncertain significance by one submitter), Cosmic (3x in Large intestine, or Haematopoietic and lymphoid tissue), MutDB, and in LOVD 3.0 (3x) databases. The variant was not identified in COGR. The variant was identified in control databases in 397 of 277154 chromosomes (1 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 24034 chromosomes (freq: 0.0004), Other in 7 of 6460 chromosomes (freq: 0.001), Latino in 36 of 34418 chromosomes (freq: 0.001), European in 300 of 126680 chromosomes (freq: 0.002), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), East Asian in 1 of 18852 chromosomes (freq: 0.00005), Finnish in 22 of 25778 chromosomes (freq: 0.0009), and South Asian in 20 of 30780 chromosomes (freq: 0.0007). The p.Gly2023 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In silico analysis predicted the variant induces or contributes to increased exon skipping (Caminsky 2016). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513642	SCV001971707	likely benign	not provided		no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002225322	SCV002504684	likely pathogenic	Tip-toe gait		no assertion criteria provided	clinical testing	Gait disorder
GenomeConnect - Brain Gene Registry	RCV000122864	SCV003931264	not provided	Ataxia-telangiectasia syndrome		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 02-03-2017 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
GenomeConnect - Invitae Patient Insights Network	RCV000513642	SCV004228873	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-18-2016 by Lab GenPath. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.