ClinVar Miner

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

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Total submissions: 4
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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 2018-01-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other strong data supporting pathogenic classification,Well-characterized mutation at same position
Invitae RCV000233536 SCV000282914 pathogenic Ataxia-telangiectasia syndrome 2018-10-10 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 not been reported in the literature in individuals with ATM-related disease. 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 RCV000130866 SCV000687426 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-10 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

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