ClinVar Genomic variation as it relates to human health

This variant causes a G>C nucleotide substitution at the +1 position of intron 19 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. Different variants affecting the same position (c.2921+1G>A and c.2921+1G>T) are considered to be disease-causing (ClinVar variation ID: 141182, 142057), suggesting that the reference nucleotide at this position is important for RNA splicing. This variant has been identified in 1/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on available evidence, this variant is classified as Likely Pathogenic.

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Observed in the compound heterozygous state in an individual with ataxia-telangiectasia and in the homozygous state in an individual with T-ALL and a history of ataxia and failure to thrive (Jeddane et al., 2013; Wagener et al., 2021); Observed in individuals with breast and/or ovarian cancer (Lilyquist et al., 2017; Carter et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25186627, 29753700, 30322717, 33840814, 23322442, 28888541)

This sequence change affects a donor splice site in intron 19 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 present in population databases (rs587781558, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with ataxia-telangiectasia (PMID: 8845835, 11298136, 12815592, 23322442). ClinVar contains an entry for this variant (Variation ID: 188097). Studies have shown that disruption of this splice site results in skipping of exon 19 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

The c.2921+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 18 of the ATM gene. A similar alteration, c.2921+1G>A (also designated as IVS21+1G>A in the literature), has been identified in a heterozygous state in multiple individuals with ataxia telangiectasia (A-T) and was shown to result in exon skipping (Gilad S et al. Hum Mol Genet, 1996 Apr;5:433-9; García-Pérez MA et al. Clin. Exp. Immunol. 2001 Mar;123:472-80; Castellvi-Bel et al. Hum. Mutat.1999;14:156-62; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94). 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 a disease-causing mutation.