ClinVar Genomic variation as it relates to human health

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.

This variant causes an A to G nucleotide substitution at the -2 position of intron 9 of the ATM gene. A RT-PCR study using cells from a carrier individual has shown that this variant activates a cryptic splice acceptor site seven nucleotides downstream of the variant position and causes the deletion of the first seven nucleotides of exon 12 (PMID: 14695534). This results in a frameshift and premature protein truncation, and lack of detectable ATM protein expression (PMID: 14695534). This variant has been observed in two unrelated individuals affected with ataxia telangiectasia (PMID: 14695534). This variant has also been observed in two related individuals affected with breast cancer (PMID: 28691344) and in two unrelated individuals affected with breast cancer with family history of breast cancer in the first degree relatives (Color internal data). 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 Pathogenic.

Canonical splice site variant demonstrated to cause aberrant splicing and result in a null allele in a gene for which loss of function is a known mechanism of disease (Eng et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS11-2A>G; This variant is associated with the following publications: (PMID: 14695534, 15039971, 30303537)

This sequence change affects an acceptor splice site in intron 9 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer or clinical features of ataxia-telangiectasia (PMID: 14695534, 30303537). This variant is also known as IVS11-2A>G. ClinVar contains an entry for this variant (Variation ID: 419300). Studies have shown that disruption of this splice site alters ATM gene expression (PMID: 14695534). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 14695534). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

The c.1236-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the ATM gene. This alteration has been identified in the compound heterozygous state in multiple individuals with ataxia telangiectasia (A-T) (Coutinho G et al. Am J Med Genet A, 2004 Apr;126A:33-40). 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 and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Eng L et al. Hum Mutat, 2004 Jan;23:67-76; 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 a disease-causing mutation.