Submissions for variant NM_000051.4(ATM):c.5558A>T (p.Asp1853Val)

gnomAD frequency: 0.00441  dbSNP: rs1801673

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122859	SCV000166117	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000120145	SCV000167094	likely benign	not specified	2014-02-28	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	RCV000128902	SCV000172763	benign	Hereditary cancer-predisposing syndrome	2014-07-01	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.
PreventionGenetics, part of Exact Sciences	RCV000120145	SCV000301675	likely benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128902	SCV000537379	benign	Hereditary cancer-predisposing syndrome	2015-10-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120145	SCV000593486	benign	not specified	2018-07-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513231	SCV000608616	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS2
Eurofins Ntd Llc (ga)	RCV000120145	SCV000701593	benign	not specified	2016-09-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000122859	SCV000800065	likely benign	Ataxia-telangiectasia syndrome	2018-05-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513231	SCV000883424	benign	not provided	2023-08-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000122859	SCV001138522	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000513231	SCV001143115	benign	not provided	2019-01-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000122859	SCV001262761	uncertain significance	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262813	SCV001440820	benign	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Genome-Nilou Lab	RCV000122859	SCV001712303	benign	Ataxia-telangiectasia syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000128902	SCV001911468	benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.5558A>T (p.Asp1853Val) missense variant has an allele frequency of 0.48%, (1282/267,858 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.67%, (797/117,840 alleles) in the European (non-Finnish) subpopulation (BA1; http://gnomad.broadinstitute.org). Therefore, it meets criteria to be classified as benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BA1 (PMID: 33280026).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798378	SCV002042677	benign	Breast and/or ovarian cancer	2020-11-25	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225361	SCV002504735	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128902	SCV002528532	benign	Hereditary cancer-predisposing syndrome	2020-09-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120145	SCV002549990	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000513231	SCV002774000	benign	not provided	2023-01-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224156	SCV003920248	likely benign	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in numerous individuals with a variety of indications, including breast cancer, chronic lymphocytic leukemia, melanoma and common variable immunodeficiency (Teraoka 2001 PMID:11505391, Concannon 2008 PMID:18701470, Navrkalova 2013 PMID:23585524, Maxwell 2016 PMID:27153395, Casula 2019 PMID:31382929, Hargreaves 2021 PMID:34009545). Of note, multiple publications classify this variant as a benign polymorphism. This variant is present in the Genome Aggregation Database (Highest reported MAF 0.6% (881/128846) including 4 homozygotes (https://gnomad.broadinstitute.org/variant/11-108175463-A-T?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:133623). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as Likely Benign.
Myriad Genetics, Inc.	RCV001262813	SCV005083960	benign	Familial cancer of breast	2024-05-23	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.
ITMI	RCV000120145	SCV000084285	not provided	not specified	2013-09-19	no assertion provided	reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000122859	SCV000732994	likely benign	Ataxia-telangiectasia syndrome		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000122859	SCV000745818	likely benign	Ataxia-telangiectasia syndrome	2016-01-22	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128902	SCV000787873	likely benign	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358294	SCV001553987	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asp1853Val variant was identified in 39 of 2578 proband chromosomes (frequency: 0.02) from individuals or families with prostate, breast and ovarian cancer and was present in 4 of 880 control chromosomes (frequency: 0.005) from healthy individuals (Angele 2004, Paglia 2010, Johnson 2007, Tapia 2008). The variant was also identified in dbSNP (ID: rs1801673) as “With Likely benign allele”,ClinVar (classified as benign by Invitae, Ambry Genetics, Color Genomics; classified as likely benign by GeneDx, Prevention Genetics), Cosmic (classified as pathogenic (score 0.97)), MutDB (clasified as polymorphism), LOVD 3.0, databases. The variant was not identified in GeneInsight-COGR, ATM-LOVD, databases. The variant was identified in control databases in 1360 (6 homozygous) of 276730 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 p.Asp1853 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Armadillo-type fold functional domain increasing the likelihood that it may have clinical significance. The study by Angele (2004) observed no significant differences in the frequency between the cases and controls. However, functional study by Tapia (2008) suggests a possible alteration of normal splicing due to variant affect an ESE sequence. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120145	SCV001905982	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000120145	SCV001924844	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128902	SCV001950174	likely benign	Hereditary cancer-predisposing syndrome	2021-09-15	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000513231	SCV001952895	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513231	SCV001967249	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000513231	SCV002036523	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000122859	SCV002084274	benign	Ataxia-telangiectasia syndrome	2019-12-09	no assertion criteria provided	clinical testing