Submissions for variant NM_000051.4(ATM):c.1254A>G (p.Gln418=)

gnomAD frequency: 0.02542  dbSNP: rs4987943

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119159	SCV000153880	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130976	SCV000185893	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.
Illumina Laboratory Services, Illumina	RCV000119159	SCV000367027	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705878	SCV000602554	benign	not provided	2023-10-14	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130976	SCV000679695	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130976	SCV000681962	benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000506744	SCV000805493	benign	not specified	2016-11-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001705878	SCV001889119	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17333338)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798372	SCV002042906	benign	Breast and/or ovarian cancer	2021-05-17	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225350	SCV002505083	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315705	SCV004017092	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000506744	SCV004027150	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315705	SCV005083833	benign	Familial cancer of breast	2024-04-26	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	RCV001705878	SCV005215714	likely benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000130976	SCV000787843	likely benign	Hereditary cancer-predisposing syndrome	2018-01-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000119159	SCV001456887	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357804	SCV001553388	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM, p.Gln418= variant was identified in 7 of 580 proband chromosomes (frequency: 0.01) from African-American, Caucasian, and Egyptian individuals or families with breast cancer or acute lymphoblastic leukemia and was present in 18 of 884 control chromosomes (frequency: 0.02) from healthy individuals (Rosenstein 2006, Meier 2005, Kim 2017). The variant was identified in dbSBP (ID: rs4987943) as "With other allele", ClinVar database (classified as benign by Invitae and Ambry Genetics; and likely benign by Illumina), Clinvitae (2x), and LOVD 3.0 (effect unknown) databases; and was not identified in the COSMIC, MutDB or LOVD-ATM databases. The variant was identified in control databases in 2296 of 271418 chromosomes (80 homozygous) at a frequency of 0.008 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 1912 of 23758 chromosomes (freq: 0.08). The c.1254A>G 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 p.Gln418= 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 summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000506744	SCV001807520	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000506744	SCV001906410	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000506744	SCV001924622	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000506744	SCV001952345	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000506744	SCV002036906	benign	not specified		no assertion criteria provided	clinical testing