ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2921+2dup (rs1565424654)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780924 SCV000918579 likely pathogenic Ataxia-telangiectasia syndrome 2018-12-10 criteria provided, single submitter clinical testing Variant summary: ATM c.2921+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing with exon 21 skipping (Teraoka_1999). The variant was absent in 246110 control chromosomes (gnomAD). The variant, c.2921+2dupT, has been reported in the literature in one homozygote individual affected with Ataxia-Telangiectasia (Teraoka_1999). These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000780924 SCV000937703 uncertain significance Ataxia-telangiectasia syndrome 2018-10-16 criteria provided, single submitter clinical testing This sequence change falls in intron 19 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous in an individual affected with ataxia-telangiectasia (PMID: 10330348). This variant is also known as IVS21+3insT in the literature. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this insertion results in exon 19 skipping of the mRNA and a truncated ATM protein (PMID: 10330348). Exon 19 is also known as exon 21 in the literature. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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