RNF43 was first reported in relation to autosomal dominant sessile serrated polyposis (SPS) cancer syndrome in 2014 (Gala et al., PMID: 24512911). SPS is a rare, genetic intestinal disease characterized by the presence of multiple (usually large) serrated colorectal polyps, associated with an increased personal and familial risk of colorectal cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found only one disease entity associated with this gene [Sessile serrated polyposis cancer syndrome] (OMIM:617108). Seven variants (missense, nonsense, frameshift, splice site) that have been reported in nine probands in seven publications (PMIDs: 27081527, 27329244, 27582512, 29330307, 35128723, 34541672, 34761457) are included in this curation (10.7 points). The mechanism of pathogenicity is reported to be heterozygous LOF. This gene-disease relationship is also supported by experimental evidence (3.6 points from animal model, expression studies, in vitro functional assays and second hits in patients' cells) (PMIDs: 18313049, 22895187, 26350900, 27329244, 32934222). Experimental evidence shows that RNF43 is an E3 ubiquitin ligase that negatively regulates Wnt signaling by inducing degradation of the Wnt receptor Frizzled, impacting intestinal cell proliferation. In summary, there is definitive evidence to support the relationship between RNF43 and autosomal dominant sessile serrated polyposis cancer syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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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