ClinVar Genomic variation as it relates to human health

This variant impacts the canonical acceptor site at intron 18 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Splicing has been reported as aberrant for this variant (PMID: 12815592). This variant has been reported in an individual affected with Ataxia-Telangiectasia (PMID: 12815592). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

Variant disrupting a canonical splice site in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual with ataxia telangiectasia, but the presence of a second pathogenic variant is unclear (Mitui et al., 2003); Observed in an individual with early-onset renal cancer and thyroid cancer (Hartman et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS20-3del4ins7; This variant is associated with the following publications: (PMID: 28152038, 12815592, 32782288)

Variant summary: ATM c.2839-3_2839delinsGATACTA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251286 control chromosomes (gnomAD). c.2839-3_2839delinsGATACTA has been reported in the literature in an individual affected with Ataxia-Telangiectasia and in an individual affected with early-onset renal cancer and thyroid cancer (Mitui_2003, LaDuca_2017, Hartman_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Lines of evidence used in support of classification: Well-characterized mutation at same position,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity

This sequence change affects an acceptor splice site in intron 18 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 6 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. Disruption of this splice site has been observed in individuals with ataxia-telangiectasia (PMID: 12815592; Invitae). This variant is also known as IVS20-3del3ins7. ClinVar contains an entry for this variant (Variation ID: 1076780). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 19 (Invitae). This variant disrupts a region of the ATM protein in which other variant(s) (p.Leu950Arg) have been determined to be pathogenic (PMID: 10873394, 12552559, 20678261, 21792198, 27989354). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.