Submissions for variant NM_000051.4(ATM):c.3993+5G>T

gnomAD frequency: 0.00287  dbSNP: rs3092842

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212007	SCV000167087	benign	not specified	2013-10-29	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	RCV000129022	SCV000172923	benign	Hereditary cancer-predisposing syndrome	2017-09-05	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	RCV001082999	SCV000262384	benign	Ataxia-telangiectasia syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212007	SCV000593482	benign	not specified	2017-05-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705901	SCV000602569	benign	not provided	2023-08-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129022	SCV000682171	benign	Hereditary cancer-predisposing syndrome	2015-09-30	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129022	SCV000747795	likely benign	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212007	SCV000805546	benign	not specified	2017-01-30	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000212007	SCV000840936	benign	not specified	2024-03-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001705901	SCV001469348	benign	not provided	2019-10-23	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225398	SCV002504707	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129022	SCV002536695	benign	Hereditary cancer-predisposing syndrome	2020-10-07	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315837	SCV004017236	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001705901	SCV004184191	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492558	SCV004240624	likely benign	Breast and/or ovarian cancer	2023-04-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315837	SCV005083952	benign	Familial cancer of breast	2024-05-21	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212007	SCV005090281	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356113	SCV001551186	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM c.3993+5G>T variant was identified in 3 of 5470 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer or lynch syndrome (Tavtigian 2009, Tung 2016, Yurgelun 2015, ). The variant was also identified in dbSNP (ID: rs3092842) as "With Likely benign allele", and in ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, ARUP, Color Genomics, Genetic Services Laboratory, University of Chicago; as likely benign by Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.), and LOVD 3.0 (1x as likely benign). The variant was identified in control databases in 248 of 276424 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 233 of 24018 chromosomes (freq: 0.01), Other in 2 of 6448 chromosomes (freq: 0.0003), Latino in 12 of 34394 chromosomes (freq: 0.0004), and European in 1 of 126028 chromosomes (freq: 0.00001); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.3993+5G>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. This variant was identified in an individual with HBOC and a co-occurring BRCA2 variant (c.6405_6409del) increasing the likelihood the ATM c.3993+5G>T variant may not have clinical significance. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705901	SCV001931036	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001705901	SCV001973798	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212007	SCV001977738	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001082999	SCV002081592	likely benign	Ataxia-telangiectasia syndrome	2019-10-30	no assertion criteria provided	clinical testing