Submissions for variant NM_000051.4(ATM):c.5497-8T>C

gnomAD frequency: 0.02183  dbSNP: rs3092829

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119146	SCV000153865	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000128919	SCV000172786	benign	Hereditary cancer-predisposing syndrome	2013-05-29	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Vantari Genetics	RCV000128919	SCV000266993	benign	Hereditary cancer-predisposing syndrome	2015-10-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000246719	SCV000301673	benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128919	SCV000537354	benign	Hereditary cancer-predisposing syndrome	2015-04-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705877	SCV000602563	benign	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000119146	SCV000743731	likely benign	Ataxia-telangiectasia syndrome	2014-10-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119146	SCV001260629	benign	Ataxia-telangiectasia syndrome	2018-03-08	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Genome-Nilou Lab	RCV000119146	SCV001750399	benign	Ataxia-telangiectasia syndrome	2021-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001705877	SCV001833472	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225348	SCV002504733	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000246719	SCV002760587	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315704	SCV004016069	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315704	SCV005083957	benign	Familial cancer of breast	2024-05-23	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Breakthrough Genomics, Breakthrough Genomics	RCV001705877	SCV005218447	likely benign	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000119146	SCV000745817	benign	Ataxia-telangiectasia syndrome	2015-11-22	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128919	SCV000787872	likely benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000119146	SCV001452318	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357689	SCV001553231	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM c.5497-8T>C variant was identified in 37 of 1416 proband chromosomes (frequency: 0.026) from individuals or families with breast cancer (Concannon 2008, Paglia 2010). The variant was also identified in dbSNP (ID: rs3092829) as “With Benign allele”, ClinVar (5x, as benign by Invitae, Ambry Genetics, Vantari, PreventionGenetics, Color Genomics), Clinvitae (3x, as benign), Cosmic (4x, in ovary carcinoma, and soft tissue Haemangioblastoma), LOVD 3.0 (1x with "does not affect function"), databases. The variant was not identified in GeneInsight-COGR, MutDB and ATM-LOVD, databases. The variant was identified in control databases in 6238 (94 homozygous) of 276468 chromosomes at a frequency of 0.0225 increasing the likelihood this could be a benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 4209 (69 homozygous) of 126224 chromosomes (freq: 0.033), other in 181 (3 homozygous) of 6446 chromosomes (freq: 0.028), European (Finnish) in 650 (10 homozygous) of 25722 chromosomes (freq: 0.025), Ashkenazi Jewish* in 236 (4 homozygous) of 10138 chromosomes (freq: 0.023), Latino in 631 (7 homozygous) of 34354 chromosomes (freq: 0.018). The c.5497-8T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358036	SCV001553673	benign	Triple-negative breast carcinoma		no assertion criteria provided	clinical testing	The ATM c.5497-8T>C variant was identified in 37 of 1416 proband chromosomes (frequency: 0.026) from individuals or families with breast cancer (Concannon 2008, Paglia 2010). The variant was also identified in dbSNP (ID: rs3092829) as “With Benign allele”, ClinVar (5x, as benign by Invitae, Ambry Genetics, Vantari, PreventionGenetics, Color Genomics), Clinvitae (3x, as benign), Cosmic (4x, in ovary carcinoma, and soft tissue Haemangioblastoma), LOVD 3.0 (1x with "does not affect function"), databases. The variant was not identified in GeneInsight-COGR, MutDB and ATM-LOVD, databases. The variant was identified in control databases in 6238 (94 homozygous) of 276468 chromosomes at a frequency of 0.0225 increasing the likelihood this could be a benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 4209 (69 homozygous) of 126224 chromosomes (freq: 0.033), other in 181 (3 homozygous) of 6446 chromosomes (freq: 0.028), European (Finnish) in 650 (10 homozygous) of 25722 chromosomes (freq: 0.025), Ashkenazi Jewish* in 236 (4 homozygous) of 10138 chromosomes (freq: 0.023), Latino in 631 (7 homozygous) of 34354 chromosomes (freq: 0.018). The c.5497-8T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000246719	SCV001798112	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000246719	SCV001906045	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000246719	SCV001924832	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000246719	SCV001954845	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000246719	SCV001965791	benign	not specified		no assertion criteria provided	clinical testing