Submissions for variant NM_000051.4(ATM):c.735C>T (p.Val245=)

gnomAD frequency: 0.01085  dbSNP: rs3218674

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162384	SCV000212697	benign	Hereditary cancer-predisposing syndrome	2014-08-01	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	RCV000204399	SCV000262457	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000253651	SCV000301683	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000204399	SCV000367024	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000162384	SCV000537370	benign	Hereditary cancer-predisposing syndrome	2015-04-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000204399	SCV000790971	likely benign	Ataxia-telangiectasia syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710681	SCV000840958	benign	not provided	2017-09-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710681	SCV001159124	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000710681	SCV001894266	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12810666)
CeGaT Center for Human Genetics Tuebingen	RCV000710681	SCV002497168	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATM: BP4, BP7, BS1, BS2
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225472	SCV002505017	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162384	SCV002537615	benign	Hereditary cancer-predisposing syndrome	2020-02-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000253651	SCV002760511	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315976	SCV004015367	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315976	SCV005083922	benign	Familial cancer of breast	2024-04-22	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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000204399	SCV000745804	benign	Ataxia-telangiectasia syndrome	2016-08-23	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162384	SCV000787881	likely benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000204399	SCV001454845	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358287	SCV001553979	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Val245= variant was identified in 44 of 3228 proband chromosomes (frequency: 0.01) from individuals or families with b-cell lymphoma tumours, chronic lymphocytic leukemia and hereditary breast and ovarian cancer and was present in 74 of 4368 control chromosomes (frequency: 0.007) from healthy individuals (Skowronska 2012, Concannon 2008, Gronbaek 2002, Heikkinen 2005, Mangone 2015, Petereit 2013, Tommiska 2006). The variant was identified in dbSNP (rs3218674) as “with likely benign, other allele, ClinVar (classified as benign by Invitae, Ambry Genetics, Color, PreventionGenetics and 2 other submitters and likely benign by True Health Diagnostics, Illumina and Counsyl) and LOVD 3.0 (observed 5x). The variant was identified in control databases in 3269 of 282,410 chromosomes (43 homozygous) at a frequency of 0.01 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: Finnish in 1057 of 25,098 chromosomes (freq: 0.04), European in 1977 of 128,822 chromosomes (freq: 0.02), Other in 78 of 7206 chromosomes (freq: 0.01), Latino in 100 of 35,408 chromosomes (freq: 0.003), African in 45 of 24,960 chromosomes (freq: 0.002), South Asian in 10 of 30,610 chromosomes (freq: 0.0003), Ahkenazi Jewish in 2 of 10,360 chromosomes (freq: 0.0002), while the variant was not observed in the East Asian population. The p.Val245= 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. The variant occurs at a non-highly conserved nucleotide 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 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	RCV000253651	SCV001906377	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000253651	SCV001919583	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000253651	SCV001952863	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000710681	SCV002036377	likely benign	not provided		no assertion criteria provided	clinical testing