ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130866 SCV000185765 pathogenic Hereditary cancer-predisposing syndrome 2019-08-29 criteria provided, single submitter clinical testing The c.2921+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 18 of the ATM gene. Another alteration at this same nucleotide position has been reported in a homozygous state in one patient with a clinical diagnosis of ataxia-telangiectasia and in a compound heterozygous state in three patients with clinical diagnoses of ataxia-telangiectasia (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Castellví-Bel S et al. Hum. Mutat. 1999;14:156-62; García-Pérez MA et al. Clin. Exp. Immunol. 2001 Mar;123:472-80; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50). In addition to the clinical data presented in the literature, RNA studies detected abnormal splicing in individuals with the c.2921+1G>T alteration (Ambry internal data). As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000233536 SCV000282914 pathogenic Ataxia-telangiectasia syndrome 2020-08-25 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 not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual with colorectal cancer (PMID: 29478780). ClinVar contains an entry for this variant (Variation ID: 142057). A different variant affecting this nucleotide (c.2921+1G>A), also referred to in the literature as 2983del83 and IVS21+1G>A), has been reported in multiple individuals affected with ataxia-telangiectasia (PMID: 8845835, 11298136). Functional studies have demonstrated that this change causes skipping of exon 19 (also referred to as exon 21), leading to a frameshift and a premature stop codon (p.Tyr947Glnfs*9). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
Color Health, Inc RCV000130866 SCV000687426 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-03 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000233536 SCV000746373 pathogenic Ataxia-telangiectasia syndrome 2017-12-03 criteria provided, single submitter clinical testing
GeneDx RCV001571421 SCV001795895 pathogenic not provided 2020-01-24 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29478780, 28152038)
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000130866 SCV001911456 pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.2921+1G>T 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 is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; There is a pathogenic variant (c.2921+1G>A) in the same position, and the in silico splicing algorithm SPiCE predicts the same impact for both variants (PS1_Supporting). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS1_Supporting (PMID: 33280026).

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