Submissions for variant NM_000051.4(ATM):c.3383A>G (p.Gln1128Arg)

gnomAD frequency: 0.00636  dbSNP: rs2229020

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000224651	SCV000167082	benign	not provided	2019-01-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17333338, 20981092, 22529920, 11996792, 24728327, 25122203, 22071889, 21933854)
Ambry Genetics	RCV000128988	SCV000172879	benign	Hereditary cancer-predisposing syndrome	2014-11-20	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.
Invitae	RCV000204666	SCV000261654	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224651	SCV000281587	likely benign	not provided	2016-04-28	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Eurofins Ntd Llc (ga)	RCV000120133	SCV000339808	benign	not specified	2016-02-29	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128988	SCV000576460	likely benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128988	SCV000682125	benign	Hereditary cancer-predisposing syndrome	2015-03-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000204666	SCV000799196	likely benign	Ataxia-telangiectasia syndrome	2018-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120133	SCV000805539	benign	not specified	2016-12-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000204666	SCV001260526	likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224651	SCV001473948	benign	not provided	2021-05-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000120133	SCV001474792	benign	not specified	2020-06-08	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225359	SCV002505346	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128988	SCV002535957	benign	Hereditary cancer-predisposing syndrome	2020-01-30	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492418	SCV002802635	likely benign	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-05-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315725	SCV004017125	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120133	SCV004027201	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ITMI	RCV000120133	SCV000084272	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000204666	SCV001462134	benign	Ataxia-telangiectasia syndrome	2020-04-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356319	SCV001551453	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Gln1128Arg variant was identified in 8 of 9204 proband chromosomes (frequency: 0.000869) from individuals or families with breast cancer, CLL, Ataxia telangiectasia and was present in 2 of 5218 control chromosomes (frequency: 0.0003) from healthy individuals (Austen 2005, Jacquemin 2011, Skowronska 2012, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs2229020) as With other allele, ClinVar (classified as benign by GenDx, Ambry Genetics, Invitae), Clinvitae (classified as benign by ClinVar, Invitae), Cosmic (pathogenic), MutDB, databases. The variant was not identified in LOVD 3.0, ATM-LOVD, databases. The variant was identified in control databases in 601(8 homozygous) of 276616 chromosomes at a frequency of 0.002 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 528 of 24022 chromosomes (freq: 0.022). The p.Gln1128 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 not very predictive of pathogenicity. The variant is located with the Armadillo-type fold functional domain increasing the likelihood that it may 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120133	SCV001906360	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120133	SCV001957493	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000120133	SCV001967814	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224651	SCV002036961	likely benign	not provided		no assertion criteria provided	clinical testing