Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003534417 | SCV001230885 | pathogenic | Familial adenomatous polyposis 1 | 2022-09-03 | criteria provided, single submitter | clinical testing | Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (PMID: 15459959; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 181833). This variant is also known as IVS3-1G>C. Disruption of this splice site has been observed in individuals with familial adenomatous polyposis (PMID: 11748858, 15459959). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the APC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. |
| Ambry Genetics | RCV002326915 | SCV002627235 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-23 | criteria provided, single submitter | clinical testing | The c.423-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 4 of the APC gene. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data; Hutter P et al. Hum. Mutat., 2001 Dec;18:550). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV002516422 | SCV004045508 | pathogenic | Familial adenomatous polyposis 1 | 2023-05-03 | criteria provided, single submitter | clinical testing | 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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959]. |
| Mayo Clinic Laboratories, |
RCV000202202 | SCV000256991 | pathogenic | not provided | no assertion criteria provided | research |