RNF43 – Hyperplastic Polyposis Syndrome

Hyperplastic polyposis syndrome (HPS), also known as serrated polyposis syndrome, is characterized by multiple serrated colorectal polyps and an elevated colorectal cancer risk. Germline truncating variants in RNF43 (HGNC:18505), a negative regulator of Wnt signaling, have been reported in affected kindreds, supporting a role in familial HPS. A heterozygous nonsense variant, c.394C>T (p.Arg132Ter), segregated with serrated polyposis in a severely affected family, with at least four affected relatives carrying the variant and manifesting multiple large serrated polyps (1 family) (PMID:27081527). In a panel study of 73 SPS patients, one additional carrier of a pathogenic RNF43 germline variant was identified, accounting for 1.4% of tested individuals (PMID:35128723). However, larger cohorts have failed to identify recurrent germline RNF43 variants in serrated polyposis, and the overall prevalence of RNF43‐mediated HPS remains below 3%. Somatic studies demonstrate that RNF43 frameshift and truncating mutations activate Wnt/β‐catenin signaling in colorectal tumors, but germline functional data are limited.

1 Assess Clinical Validity

ClinGen classification: Limited
Rationale: Single kindred with segregation (≥4 affected relatives) for c.394C>T (p.Arg132Ter) ([PMID:27081527]) and one additional proband in a 73‐patient panel ([PMID:35128723]); absence of replication in larger cohorts limits evidence strength.

2 Genetic Evidence

• Inheritance: Autosomal dominant monoallelic truncating variants.
• Segregation: At least 4 affected relatives co‐segregating c.394C>T (p.Arg132Ter) in one family ([PMID:27081527]).
• Case series: 1 kindred and 1 sporadic carrier among 73 tested.
• Variant spectrum: Predominantly truncating (nonsense, frameshift) variants; reported c.394C>T (p.Arg132Ter).

3 Functional / Experimental Evidence

• Mechanism: Haploinsufficiency of RNF43 leads to increased Wnt signaling; somatic truncating mutations in RNF43 enhance Wnt/β‐catenin activity in colorectal and serrated lesions.
• Assays: Somatic mutation analyses show loss of RNF43 expression in MSI‐H colorectal tumors; IHC confirms decreased RNF43 in tumors with frameshifts ([PMID:26297255]).

4 Conflicting Evidence

Germline RNF43 mutations are infrequent; several SPS cohorts (n=26 and larger) lacked RNF43 truncating variants, suggesting low penetrance and alternative etiologies.

5 Conclusion

RNF43 truncating germline variants represent a rare, autosomal dominant cause of serrated polyposis syndrome. Limited segregation and low carrier frequency constrain the clinical validity to “Limited.” Genetic testing for RNF43 may be considered in familial SPS cases with multiple affected relatives but is unlikely to yield positive findings in sporadic presentations. Further studies are needed to define penetrance and to corroborate functional impact of germline RNF43 loss.

Key takeaway: Germline RNF43 truncating variants are an uncommon genetic etiology for hyperplastic polyposis syndrome; targeted testing should focus on families with multiple serrated‐polyp–affected members.

References

• Human genome variation • 2015 • A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred. PMID:27081527
• Journal of gastroenterology and hepatology • 2022 • Germline variant testing in serrated polyposis syndrome. PMID:35128723
• Human pathology • 2015 • Frequent frameshift mutations in 2 mononucleotide repeats of RNF43 gene and its regional heterogeneity in gastric and colorectal cancers. PMID:26297255

Evidence Based Scoring (AI generated)