Submissions for variant NM_000051.4(ATM):c.657T>C (p.Cys219=)

gnomAD frequency: 0.02841  dbSNP: rs2235003

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129174	SCV000183907	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Invitae	RCV000206853	SCV000262252	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000116429	SCV000301682	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000206853	SCV000367022	benign	Ataxia-telangiectasia syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000129174	SCV000537402	benign	Hereditary cancer-predisposing syndrome	2015-04-08	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710677	SCV000840953	benign	not provided	2017-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000710677	SCV001900473	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798369	SCV002042758	benign	Breast and/or ovarian cancer	2021-05-26	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225340	SCV002505007	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000116429	SCV002760509	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315666	SCV004016497	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000116429	SCV000150354	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
True Health Diagnostics	RCV000129174	SCV000787877	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000206853	SCV001454840	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357712	SCV001553261	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Cys219= variant was identified in 1 of 404 proband chromosomes (frequency: 0.0024) from individuals or families with cancer, although the cancer type was unspecified (Petereit 2013). The variant was also identified in 4 of 186 control chromsomes (freq. 0.022) in unaffected individuals (Thorstenson 2001). The variant was also identified in dbSBP (ID: rs2235003) as “With other allele,” ClinVar (as likely benign by Genetics Services Laboratory University of Chicago and Illumina and as benign by Ambry Genetics, Invitae, Prevention Genetics, and Color Genomics), Clinvitae, and ATM-LOVD databases. The variant was not identified in Cosmic, MutDB, LOVD 3.0 databases. The variant was identified in control databases in 2436 of 276942 chromosomes at a frequency of 0.008796 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the African population at a frequency greater than 1% in 2217 (101 homozygous) of 23994 chromosomes (freq: 0.092), and at lower frequencies in the following populations: Other in 22 of 6448 chromosomes (freq. 0.003), Latino in 166 (1 homozygous) of 34366 chromosomes (freq. 0.0048), and European (Non-Finnish) in 25 of 126568 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency benign variant. The p.Cys219Cys variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000116429	SCV001808539	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000116429	SCV001906265	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000116429	SCV001919766	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000116429	SCV001956851	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000116429	SCV002037081	benign	not specified		no assertion criteria provided	clinical testing