ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2921+1G>A (rs587781558)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129576 SCV000184358 pathogenic Hereditary cancer-predisposing syndrome 2019-06-07 criteria provided, single submitter clinical testing The c.2921+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 18 of the ATM gene. This mutation is also designated as IVS21+1G>A and 2839del83 in published literature. This mutation has previously been reported in the literature in clinically affected individuals with ataxia-telangiectasia in both compound heterozygous and homozygous forms (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Castellvi-Bel S et al. Hum. Mutat. 1999;14:156-62; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94). The c.2921+1G>A mutation has also been shown to lead to exon skipping resulting in a frameshift and premature protein truncation (García-Pérez MA et al. Clin. Exp. Immunol. 2001 Mar;123:472-80). RNA studies have demonstrated that this alteration results in the same splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000169059 SCV000220222 likely pathogenic Ataxia-telangiectasia syndrome 2014-04-03 criteria provided, single submitter literature only
GeneDx RCV000215085 SCV000278817 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.2921+1G>A or IVS19+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 19 of the ATM gene. The variant, also reported as IVS21+1G>A using alternate nomenclature and exon numbering, destroys a canonical splice donor site and has been shown to result in exonic skipping, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Garcia-Perez 2001). This variant has been reported in patients with classic ataxia-telangiectasia in both the homozygous and compound heterozygous states and in at least one individual with endometrial cancer (Gilad 1996, Garcia-Perez 2001, Mitui 2003, Jeddane 2013, Ring 2016). We consider this variant to be pathogenic.
Color Health, Inc RCV000129576 SCV000537641 pathogenic Hereditary cancer-predisposing syndrome 2020-05-26 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the canonical +1 position of intron 19 splice donor site of the ATM gene. This variant is also known as IVS21+1G>A and 2839del83 in the literature. Functional RNA studies have shown that this variant causes skipping of exon 19 (exon 21 in U33841 transcript), which results in a premature protein truncation (PMID: 11298136). This variant has been observed in individuals with ataxia-telangiectasia in homozygous state or compound heterozygous state with another pathogenic variant (PMID: 8845835, 11298136, 12815592, 12673797, 12815592, 23322442). This variant has been identified in 6/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV000169059 SCV000546716 pathogenic Ataxia-telangiectasia syndrome 2020-10-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587781558, ExAC 0.01%). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 8845835, 11298136, 12815592, 23322442, 12673797). In two individuals this variant was found in the homozygous state, while in four individuals it was found as compound heterozygous with a second pathogenic ATM variant. It is also known as IVS21+1G>A and 2839del83 in the literature. ClinVar contains an entry for this variant (Variation ID: 141182). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507017 SCV000602557 pathogenic not specified 2016-08-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169059 SCV000694238 pathogenic Ataxia-telangiectasia syndrome 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The ATM c.2921+1G>A variant involves the alteration of a conserved intronic nucleotide, which 4/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicts the removal of an ESE binding site. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121072 (1/40355), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasia. Multiple publications cite the variant in A-T patients that were homozygous or compound heterozygous. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762820 SCV000893178 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000129576 SCV001911455 pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.2921+1G>A variant is located in the canonical donor splice site of intron 19, and it is predicted to cause the skipping of exon 19 and disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.000021 (0.002%, 5/236,780 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.000067 (0.006721%, 1/14878 alleles) in the African subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been described in trans with a (likely) pathogenic ATM variant in three ataxia-telangiectasia probands and in homozygosis in two additional ataxia-telangiectasia probands, which awards 4 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_VeryStrong ; PMID: 8968760; PMID: 11298136; PMID: 12815592). Moreover, there is an RNA assay which confirms the deletion of 83bp of exon 19 leading to NMD (PS3_Supporting; PMID: 11298136). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3_VeryStrong + PS3_Supporting (PMID: 33280026).
Franklin by Genoox RCV000215085 SCV000916301 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV000169059 SCV001452057 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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