Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.422+2T>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]
APC Gene-Disease associations (from GenCC):
classic or attenuated familial adenomatous polyposis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
desmoid tumor
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
familial adenomatous polyposis 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
gastric adenocarcinoma and proximal polyposis of the stomach
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-112767392-T-A is Pathogenic according to our data. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112767392-T-A is described in CliVar as Likely_pathogenic. Clinvar id is 2584052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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. -
The c.422+2T>A intronic variant results from a T to A substitution two nucleotides after coding exon 3 in the APC gene. This variant was reported in individuals with features consistent with familial adenomatous polyposis (Olschwang S et al. Am J Hum Genet, 1993 Feb;52:273-9; Lagarde A et al. J Med Genet, 2010 Oct;47:721-2; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, 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 likely pathogenic. -