ClinVar Genomic variation as it relates to human health

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29478780, 28152038)

The c.2921+1G>T variant is located in the canonical donor splice site of intron 19, and it is predicted to cause the skipping of exon 19 and disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). There is a pathogenic variant (c.2921+1G>A) in the same position, and the in silico splicing algorithm SPiCE predicts the same impact for both variants (PS1_Supporting). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS1_Supporting (PMID: 33280026).

Variant summary: ATM c.2921+1G>T 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: Three predict the variant abolishes the canonical 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251304 control chromosomes. c.2921+1G>T has been reported in the literature in two individuals affected with Colorectal cancer and early onset Rhabdomyosarcoma, respectively (examples: AlDubayan_2018, Kim_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different change c.2921+1G>A at this location has been reported in individuals with breast cancer and ovarian cancer and with ataxia-telangiectasia (Pathogenic at Labcorp with Ataxia Telangiectasia, 17 Pathogenic/clinical testing in ClinVar). The following publications have been ascertained in the context of this evaluation (PMID: 29478780, 34308104). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This variant causes a G to T 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. A different variant affecting the same nucleotide position (c.2921+1G>A) is considered to be disease-causing (ClinVar variation ID: 141182), suggesting that the reference nucleotide at this position is important for normal RNA splicing. This variant has been reported in individuals affected with breast cancer (PMID: 34204722) or colorectal cancer (PMID: 29478780). 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.

The c.2921+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 18 of the ATM gene. Another alteration at this same nucleotide position has been reported in a homozygous state in one patient with a clinical diagnosis of ataxia-telangiectasia and in a compound heterozygous state in three patients with clinical diagnoses of ataxia-telangiectasia (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Castellví-Bel S et al. Hum. Mutat. 1999;14:156-62; García-Pérez MA et al. Clin. Exp. Immunol. 2001 Mar;123:472-80; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50). In addition to the clinical data presented in the literature, RNA studies detected abnormal splicing in individuals with the c.2921+1G>T alteration (Ambry internal data). As such, this alteration is classified as a disease-causing mutation.

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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with ataxia-telangiectasia, colorectal cancer (PMID: 8845835, 11298136, 29478780). ClinVar contains an entry for this variant (Variation ID: 142057). Studies have shown that disruption of this splice site results in skipping of exon 19 and introduces a premature termination codon (PMID: 11298136; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

This variant is considered 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.