ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6067G>A (p.Gly2023Arg) (rs11212587)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000513642 SCV000149130 likely benign not provided 2021-06-17 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26976419, 26787654, 26094658, 27153395, 21933854, 29445900, 26053404, 19404735, 11505391, 17393301, 12810666, 22529920, 23091097, 17968022, 12149228, 16461462, 21787400, 19781682, 24728327, 25624042, 26898890, 27664052, 25980754, 24584352, 27150160, 26483394, 26822149, 27882345, 25625042, 27498913, 28608266, 29678143, 23555315, 26822949, 27621404, 28779002, 30197789, 31108397, 30309722, 31159747, 30303537, 32854451)
Invitae RCV000122864 SCV000166122 benign Ataxia-telangiectasia syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115221 SCV000183877 likely benign Hereditary cancer-predisposing syndrome 2018-07-27 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Subpopulation frequency in support of benign classification
PreventionGenetics,PreventionGenetics RCV000120151 SCV000301678 benign not specified criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513642 SCV000608617 likely benign not provided 2021-04-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115221 SCV000687670 likely benign Hereditary cancer-predisposing syndrome 2015-02-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000513642 SCV000694314 benign not provided 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The ATM c.6067G>A (p.Gly2023Arg) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 397/277154 (1 homozygote) control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.002368 (300/126680). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple publications have cited the variant in affected BrC pts, along with multiple somatic occurrences in MCL and CLL pts. Skowronska_2012 suggestions, biallelic ATM inactivation in CLL patients was associated with disease progression and reduced survival. However, the variant has been reported to co-occur with a BRCA1 variant, although the exact variant was not indicated (Thorstenson_2003). In addition, two internal LCA samples report the variant to co-occur with a pathogenic ATM variant, c.6095G>A (p.Arg20232Lys) and BRCA1 variant, c.1326T>A (p.Cys442X). In addition, multiple clinical diagnostic laboratories cite the variant as "likely benign/benign." Taken together, this variant is classified as benign.
GeneKor MSA RCV000115221 SCV000821865 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000122864 SCV000838565 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000513642 SCV000840948 likely benign not provided 2019-12-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122864 SCV001263992 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 RCV001253480 SCV001429203 uncertain significance Familial cancer of breast 2018-12-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000513642 SCV001469357 likely benign not provided 2019-12-19 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000513642 SCV001713581 uncertain significance not provided 2021-02-18 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000122864 SCV001781325 likely benign Ataxia-telangiectasia syndrome 2021-07-14 criteria provided, single submitter clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000115221 SCV001911470 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.6067G>A (p.Gly2023Arg) variant has an allele frequency of 0.0014 (0.14%, 374/268,256 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0023 (0.232%, 274/118,126 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026).
ITMI RCV000120151 SCV000084292 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000115221 SCV000805219 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-16 no assertion criteria provided clinical testing
Natera, Inc. RCV000122864 SCV001452119 likely benign Ataxia-telangiectasia syndrome 2020-04-18 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356569 SCV001551777 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Gly2023Arg variant was identified in 15 of 8674 proband chromosomes (frequency: 0.002) from individuals or families with CLL, lymphoid neoplasms, colorectal or breast cancer and was identified in 2 of 1602 chromosomes (frequency: 0.001) from healthy individuals (Broeks 2008, Gronbaek 2002, Mangone 2015, Paglia 2010, Podralska 2018, Skowronska 2012, Thorstenson 2003, Yurgelun 2015, Balmana 2016, Tung 2016). The variant was also identified in dbSNP (ID: rs11212587) as "With other allele", ClinVar (classified as benign by two clinical laboratories; as likely benign by Invitae, Ambry Genetics and three other submitters; as uncertain significance by one submitter), Cosmic (3x in Large intestine, or Haematopoietic and lymphoid tissue), MutDB, and in LOVD 3.0 (3x) databases. The variant was not identified in COGR. The variant was identified in control databases in 397 of 277154 chromosomes (1 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 24034 chromosomes (freq: 0.0004), Other in 7 of 6460 chromosomes (freq: 0.001), Latino in 36 of 34418 chromosomes (freq: 0.001), European in 300 of 126680 chromosomes (freq: 0.002), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), East Asian in 1 of 18852 chromosomes (freq: 0.00005), Finnish in 22 of 25778 chromosomes (freq: 0.0009), and South Asian in 20 of 30780 chromosomes (freq: 0.0007). The p.Gly2023 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) do not predict a difference in splicing. In silico analysis predicted the variant induces or contributes to increased exon skipping (Caminsky 2016). 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000513642 SCV001809752 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000513642 SCV001906079 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000513642 SCV001929245 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000513642 SCV001959733 likely benign not provided no assertion criteria provided clinical testing

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