The AXIN2 protein interacts with APC and GSK3 to organize a multiprotein complex, which leads to the degradation of beta-catenin in the Wnt signaling pathway. AXIN2 was first reported in relation to autosomal dominant oligodontia-cancer predisposition syndrome in 2004 (Lammi L et al., PMID: 15042511). Oligodontia-cancer predisposition syndrome is characterized by congenital absence of six or more permanent teeth in association with an increased risk for malignancies, ranging from gastrointestinal polyposis to early-onset colorectal cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, the described phenotypic dental manifestations and tumor/cancer spectrum have been lumped into one disease entity: oligodontia-cancer predisposition syndrome (OMIM: 608615; MONDO: 0012075). Nine variants (missense, nonsense, and frameshift) that have been reported in 9 families in 7 publications (PMIDs: 15042511, 21416598, 23838596, 27696107, 28195393, 30671715, 34637023) were included in this curation. Co-segregation of AXIN2 variants with disease in these families also provide additional evidence to support the gene-disease relationship. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (1.5 points). Compared to the controls, Wnt signaling was hyperactivated in the 293 cell line with an AXIN2 truncating variant (c.2083delG) identified from patients with colorectal cancer (PMID: 11017067). Koinuma et al. observed that AXIN2 is silenced by DNA methylation in the MSI+ (microsatellite instability) colorectal carcinoma specimens. In summary, AXIN2 is definitively associated with autosomal dominant oligodontia-cancer predisposition syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ClinGen Hereditary Cancer GCEP on 10/27/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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