Submissions for variant NM_000051.4(ATM):c.2442C>A (p.Asp814Glu)

dbSNP: rs3218695

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120123	SCV000167071	benign	not specified	2013-12-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000129054	SCV000183749	benign	Hereditary cancer-predisposing syndrome	2014-08-29	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	RCV000206885	SCV000262027	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129054	SCV000682054	benign	Hereditary cancer-predisposing syndrome	2020-11-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000206885	SCV000743723	benign	Ataxia-telangiectasia syndrome	2016-02-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120123	SCV000805516	benign	not specified	2017-03-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000206885	SCV001262550	benign	Ataxia-telangiectasia syndrome	2017-04-27	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.
Athena Diagnostics	RCV000120123	SCV001879395	benign	not specified	2020-10-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120123	SCV002047305	benign	not specified	2020-10-15	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225357	SCV002505305	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129054	SCV002532133	benign	Hereditary cancer-predisposing syndrome	2020-09-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120123	SCV002760532	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492417	SCV002802987	benign	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-07-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149819	SCV003837834	benign	Breast and/or ovarian cancer	2022-05-31	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315723	SCV004017181	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001573497	SCV004184188	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ATM: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001573497	SCV004564658	benign	not provided	2023-01-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315723	SCV005083893	benign	Familial cancer of breast	2024-05-08	criteria provided, single submitter	clinical testing	This variant is considered benign. 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	RCV001573497	SCV005231004	benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120123	SCV000084261	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000206885	SCV000745809	benign	Ataxia-telangiectasia syndrome	2017-03-24	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000206885	SCV001462069	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357064	SCV001552397	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asp814Glu variant was identified in 1 of 9370 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer and was present in 6 of 11286 control chromosomes (frequency: 0.0005) from healthy individuals (Johnson 2007, Mangone 2015, Tavtigian 2009). The variant was also identified in the following databases: dbSNP (ID: rs3218695) as "With Benign, Likely benign allele", ClinVar (4x, benign), and Clinvitae (3x, benign). The variant was not identified in Cosmic, MutDB, LOVD 3.0, or the ATM-LOVD databases. The variant was identified in control databases in 646 of 276916 chromosomes (8 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 567 of 24008 chromosomes (freq: 0.02), Other in 9 of 6464 chromosomes (freq: 0.001), Latino in 51 of 34412 chromosomes (freq: 0.001), European in 18 of 126598 chromosomes (freq: 0.0001), and South Asian in 1 of 30764 chromosomes (freq: 0.00003). The variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asp814 residue is conserved in mammals but not in more distantly related organisms. However computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is also not very predictive of pathogenicity. 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)	RCV001573497	SCV001799460	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120123	SCV001905837	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120123	SCV001958836	benign	not specified		no assertion criteria provided	clinical testing