ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5558A>T (p.Asp1853Val) (rs1801673)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122859 SCV000166117 benign Ataxia-telangiectasia syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000120145 SCV000167094 likely benign not specified 2014-02-28 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 RCV000128902 SCV000172763 benign Hereditary cancer-predisposing syndrome 2014-07-01 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.
PreventionGenetics,PreventionGenetics RCV000120145 SCV000301675 likely benign not specified criteria provided, single submitter clinical testing
Color Health, Inc RCV000128902 SCV000537379 benign Hereditary cancer-predisposing syndrome 2015-10-15 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120145 SCV000593486 benign not specified 2018-07-30 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513231 SCV000608616 likely benign not provided 2021-05-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120145 SCV000701593 benign not specified 2016-09-27 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000122859 SCV000745818 likely benign Ataxia-telangiectasia syndrome 2016-01-22 criteria provided, single submitter clinical testing
Counsyl RCV000122859 SCV000800065 likely benign Ataxia-telangiectasia syndrome 2018-05-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283201 SCV000883424 benign none provided 2019-09-05 criteria provided, single submitter clinical testing
Mendelics RCV000122859 SCV001138522 likely benign Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000513231 SCV001143115 benign not provided 2019-01-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122859 SCV001262761 uncertain significance 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262813 SCV001440820 benign Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous.
Nilou-Genome Lab RCV000122859 SCV001712303 benign Ataxia-telangiectasia syndrome 2021-05-18 criteria provided, single submitter clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000128902 SCV001911468 benign Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.5558A>T (p.Asp1853Val) missense variant has an allele frequency of 0.48%, (1282/267,858 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.67%, (797/117,840 alleles) in the European (non-Finnish) subpopulation (BA1; http://gnomad.broadinstitute.org). Therefore, it meets criteria to be classified as benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BA1 (PMID: 33280026).
ITMI RCV000120145 SCV000084285 not provided not specified 2013-09-19 no assertion provided reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000122859 SCV000732994 likely benign Ataxia-telangiectasia syndrome no assertion criteria provided clinical testing
True Health Diagnostics RCV000128902 SCV000787873 likely benign Hereditary cancer-predisposing syndrome 2017-11-14 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358294 SCV001553987 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Asp1853Val variant was identified in 39 of 2578 proband chromosomes (frequency: 0.02) from individuals or families with prostate, breast and ovarian cancer and was present in 4 of 880 control chromosomes (frequency: 0.005) from healthy individuals (Angele 2004, Paglia 2010, Johnson 2007, Tapia 2008). The variant was also identified in dbSNP (ID: rs1801673) as “With Likely benign allele”,ClinVar (classified as benign by Invitae, Ambry Genetics, Color Genomics; classified as likely benign by GeneDx, Prevention Genetics), Cosmic (classified as pathogenic (score 0.97)), MutDB (clasified as polymorphism), LOVD 3.0, databases. The variant was not identified in GeneInsight-COGR, ATM-LOVD, databases. The variant was identified in control databases in 1360 (6 homozygous) of 276730 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asp1853 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Armadillo-type fold functional domain increasing the likelihood that it may have clinical significance. The study by Angele (2004) observed no significant differences in the frequency between the cases and controls. However, functional study by Tapia (2008) suggests a possible alteration of normal splicing due to variant affect an ESE sequence. 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 RCV000120145 SCV001905982 benign not specified no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000120145 SCV001924844 benign not specified no assertion criteria provided clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000128902 SCV001950174 likely benign Hereditary cancer-predisposing syndrome 2021-09-15 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000513231 SCV001952895 likely benign not provided no assertion criteria provided clinical testing

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