ClinVar Miner

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

gnomAD frequency: 0.01137  dbSNP: rs3092857
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Total submissions: 26
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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: 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 RCV000203947 SCV000262038 benign Ataxia-telangiectasia syndrome 2021-12-17 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,PreventionGenetics 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 2020-04-27 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
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

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