Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
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. |
| Labcorp Genetics |
RCV000780924 | SCV000937703 | uncertain significance | Ataxia-telangiectasia syndrome | 2024-07-29 | 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 10330348). ClinVar contains an entry for this variant (Variation ID: 633062). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 19, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10330348). 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. |
| Baylor Genetics | RCV003472315 | SCV004203727 | likely pathogenic | Familial cancer of breast | 2023-10-30 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004669105 | SCV005167833 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-04-08 | criteria provided, single submitter | clinical testing | The c.2921+2dupT intronic variant, results from a duplication of one nucleotide at nucleotide position 2921 after intron 18 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. |
| Fulgent Genetics, |
RCV005049689 | SCV005681250 | likely pathogenic | Familial cancer of breast; Ataxia-telangiectasia syndrome | 2024-03-30 | criteria provided, single submitter | clinical testing |