Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000205665 | SCV000261323 | likely pathogenic | Ataxia-telangiectasia syndrome | 2015-10-16 | criteria provided, single submitter | clinical testing | Despite the uncertainty about the effect this variant will have on mRNA splicing and protein function, and in the absence of experimental evidence, it has been classified as Likely Pathogenic. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter consensus mRNA splicing, leading to the out-of-frame skipping of exon 54. However, these predictors also suggest that alternative splicing could occur at an activated cryptic splice site 3 nucleotides into exon 54, leading to two amino acid changes with uncertain impact on protein function (p.Lys2643_Gly2644delinsSer). Alternatively, splicing could arise at a naturally-occurring cryptic splice site 34 nucleotides upstream of exon 54, leading to the out-of-frame premature truncation of the ATM protein. However, these predictions have not been confirmed by published transcriptional studies. While this particular variant has not been reported in the literature, truncating variants in ATM are known to be pathogenic (PMID: 10817650, 19781682). This sequence change affects an acceptor splice site in intron 53. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. |
Ambry Genetics | RCV002415871 | SCV002679532 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-12-11 | criteria provided, single submitter | clinical testing | The c.7928-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 53 in 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 acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. This variant has been detected in trans with pathogenic mutation in ATM in an individual without clinical features consistent with ataxia-telangiectasia (Ambry internal data). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. |