Submissions for variant NM_000051.4(ATM):c.2193C>T (p.Tyr731=)

gnomAD frequency: 0.01543  dbSNP: rs2229019

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128878	SCV000172735	benign	Hereditary cancer-predisposing syndrome	2014-11-25	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206183	SCV000262430	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000206183	SCV000367033	benign	Ataxia-telangiectasia syndrome	2018-01-13	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	RCV000128878	SCV000682039	benign	Hereditary cancer-predisposing syndrome	2015-04-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679102	SCV000805512	benign	not specified	2015-09-14	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710665	SCV000840924	benign	not provided	2018-05-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710665	SCV001472244	benign	not provided	2023-08-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000710665	SCV001945465	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	RCV002225412	SCV002505206	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128878	SCV002534221	benign	Hereditary cancer-predisposing syndrome	2020-03-22	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149877	SCV003837625	benign	Breast and/or ovarian cancer	2021-07-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315858	SCV004016619	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000679102	SCV004027171	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710665	SCV004133246	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	ATM: BP4, BP7
Myriad Genetics, Inc.	RCV003315858	SCV005083868	benign	Familial cancer of breast	2024-05-07	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Breakthrough Genomics, Breakthrough Genomics	RCV000710665	SCV005231002	benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000128878	SCV000805211	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000206183	SCV001461022	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354816	SCV001549522	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Tyr731Tyr variant was identified in 3 of 712 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer or leukemia (Mangone 2015, Gumy Pause 2003, Dörk 2001). The variant was also identified in dbSNP (ID: rs2229019) as "With other allele", in ClinVar (classified as 2x benign, 1x likely benign), Clinvitae (classified as 1x benign, 1x conflicting interpretations of pathogenicity), and Cosmic (1x as neutral). The variant was not identified in the MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1336 of 276956 (35 homozygous) chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1213 of 24022 chromosomes (freq: 0.05). The p.Tyr731Tyr 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000679102	SCV001905922	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000679102	SCV001922173	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679102	SCV001951867	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000679102	SCV001978370	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000679102	SCV002035870	benign	not specified		no assertion criteria provided	clinical testing