Submissions for variant NM_000051.4(ATM):c.2685A>G (p.Leu895=)

gnomAD frequency: 0.01393  dbSNP: rs3218687

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128898	SCV000172758	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	RCV000205569	SCV000262432	benign	Ataxia-telangiectasia syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000205569	SCV000367038	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	RCV000128898	SCV000682070	benign	Hereditary cancer-predisposing syndrome	2015-04-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679105	SCV000805525	benign	not specified	2016-10-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710668	SCV000840930	benign	not provided	2018-05-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710668	SCV001477727	benign	not provided	2024-07-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000710668	SCV001868147	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17333338)
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225418	SCV002505334	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128898	SCV002534565	benign	Hereditary cancer-predisposing syndrome	2020-03-22	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149882	SCV003837675	benign	Breast and/or ovarian cancer	2021-07-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315863	SCV004016642	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000679105	SCV004027188	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315863	SCV005083919	benign	Familial cancer of breast	2024-05-10	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	RCV000710668	SCV005231010	benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000128898	SCV000805215	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000205569	SCV001452046	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355890	SCV001550904	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Leu895= variant was identified in 1 of 502 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer or leukemia and was not identified in 396 control chromosomes from healthy individuals (Meier 2005, Austen 2008). The variant was also identified in the following databases: dbSNP (ID: rs3218687) as “With other allele”, in ClinVar (classified 2x as benign, 1x as likely benign), Clinvitae (classified 1x as benign, 1x as 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 1217 of 277096 (32 homozygous) chromosomes at a frequency of 0.004 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 1105 of 24026 chromosomes (freq: 0.046). The p.Leu895= 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000679105	SCV001744392	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679105	SCV001808254	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000679105	SCV001905941	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000679105	SCV001922429	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679105	SCV001959810	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000679105	SCV001978440	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000710668	SCV002037031	likely benign	not provided		no assertion criteria provided	clinical testing