APC variants have been associated with familial adenomatous polyposis (FAP) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Per criteria outlined by the ClinGen Lumping an1d Splitting Working Group, we found differences in phenotypic variability. Therefore, this curation focuses solely on autosomal dominant GAPPS. The gene-disease relationship between APC and FAP was curated separately. APC was first reported in relation to autosomal dominant GAPPS (MONDO:0017790) in family pedigrees displaying fundic gland polyps but lacking a causal gene (PMID: 21813476). Li et al summarized these families, added additional families, identified causal variants through linkage analysis of a large family with 27 affected members to a region in the APC promoter and performed experimental assays (PMID:27087319). This autosomal dominant condition causes numerous fundic gland polyps and is associated with an increased incidence of gastric cancer. At least 5 probands from families with variants segregating with disease demonstrated rare, noncoding promoter variants that alter the YY1 transcription factor binding site in the APC promoter. There are multiple additional publications, including the following PMIDs: 27343414, 29141268, 31409086, 33242120. Through cases and segregation data, the maximum score for genetic evidence has been reached (12 points). This gene-disease association is also supported by experimental evidence (3 points) including decreased transcriptional activity in luciferase reporter plasmids with the YY1 binding motif disrupted across 4 cancer cell lines, EMSA assays display binding of YY1 and DNA motifs in two cancer cell lines and quantification of YY1 binding to the wild-type APC promoter (PMID:27087319). In summary, APC promoter 1B variants in the YY1 binding motif are definitively associated with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS, MONDO:0017790). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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