Submissions for variant NM_000051.4(ATM):c.3118A>G (p.Met1040Val)

gnomAD frequency: 0.01233  dbSNP: rs3092857

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221465	SCV002499278	benign	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.3118A>G (p.Met1040Val) variant has a GnomAD (v2.1.1) filtering allele frequency of 4.2% (AFR) which is above the ATM BA1 threshold of 0.5% (BA1). This variant has been observed in a homozygous state in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 500031, 61756). In silico protein predictors (BayesDel, score:-0.45, AGVGD, Class C0) predict that this alteration is not deleterious (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel.
GeneDx	RCV000116423	SCV000167077	benign	not specified	2013-11-26	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	RCV000123734	SCV000212921	benign	Hereditary cancer-predisposing syndrome	2014-11-21	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	RCV000203947	SCV000262038	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224788	SCV000281553	likely benign	not provided	2015-08-19	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
PreventionGenetics, part of Exact Sciences	RCV000116423	SCV000301659	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000203947	SCV000367040	benign	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000123734	SCV000576459	likely benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224788	SCV000602561	benign	not provided	2023-10-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000123734	SCV000682103	benign	Hereditary cancer-predisposing syndrome	2015-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000224788	SCV000694249	benign	not provided	2016-06-06	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.3118A>G (p.Met1040Val) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 459/122598 control chromosomes (10 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0413846 (428/10342, 10 homozygotes). This frequency is about 10 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Variant has been reported by multiple studies in both patients and healthy controls, supporting the non-pathogenic nature of this variant. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Considering the high allele frequency of the variant and the homozygous occurrences in the African subpopulation, it was classified as Benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001797989	SCV002042037	benign	Breast and/or ovarian cancer	2020-06-16	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225257	SCV002505343	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000116423	SCV002760547	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002221465	SCV005083884	benign	Familial cancer of breast	2024-05-13	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. 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].
Breakthrough Genomics, Breakthrough Genomics	RCV000224788	SCV005231014	benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000003166	SCV000023324	pathogenic	B-cell non-Hodgkin lymphoma	1997-09-01	no assertion criteria provided	literature only
ITMI	RCV000116423	SCV000084268	not provided	not specified	2013-09-19	no assertion provided	reference population
Genetic Services Laboratory, University of Chicago	RCV000116423	SCV000150348	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
True Health Diagnostics	RCV000123734	SCV000787858	likely benign	Hereditary cancer-predisposing syndrome	2018-01-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000116423	SCV001550824	benign	not specified		no assertion criteria provided	clinical testing	The ATM p.Met1040Val variant was identified in 18 of 1214 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer or non-Hodgkin lymphoma (Thorstenson 2001, Bretsky 2003, Sipahimalani 2007). The variant was also identified in ClinVar (benign 4x: GeneDx, Ambry Genetics, Invitae, Prevention Genetics; likely benign 3x: Mercy Hospital, Illumina, University of Chicago; not provided 1x: ITMI) unconfirmed somatic 1x: OMIM), COSMIC (2 lymphoid neoplasms, somatic status unknown), MutDB (link to UniProtKB/Swiss-Prot database, variant is unclassified with poor conservation across species), databases. The variant was not identified in the GeneInsight-COGR, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1095 (27 homozygous) of 277102 chromosomes at a frequency of 0.004 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 1012 of 24020 chromosomes (freq: 0.042). The p.Met1040Val residue is conserved in 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, and HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224788	SCV001741410	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000116423	SCV001808432	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000116423	SCV001905781	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000116423	SCV001923721	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000116423	SCV001931777	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000116423	SCV001955703	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000116423	SCV002036771	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000203947	SCV002079754	benign	Ataxia-telangiectasia syndrome	2019-11-08	no assertion criteria provided	clinical testing