I've finished searching and I'm writing the report now. RNF43 is the causal gene. I confirmed the disease identifiers and ClinGen classification from GenCC. For the literature, I read the 2024 Danish paper in full and only search-result abstracts for the rest. Several PMIDs are not confirmed and are marked as such.

Sessile Serrated Polyposis Cancer Syndrome (SSPCS): research report

Causal gene: RNF43 (HGNC:18505, 17q22; OMIM gene 612482). Disease: MONDO:0014919, OMIM:617108, autosomal dominant. Date: 2026-10-26.

Source classes. Primary literature is labelled "primary". Structured databases (ClinGen via GenCC) are labelled "database". Items I recalled from memory without checking are labelled "unverified lead". Where I found nothing, I say so.

Key points

• ClinGen classifies the RNF43–SSPCS relationship as Definitive (autosomal dominant, evaluated 2022-12-30). The 2024 Danish series calls that framing into question.
• The mechanism is heterozygous loss of function. Loss of RNF43 stabilises Frizzled at the cell surface, so cells respond more strongly to Wnt ligand. This is ligand-dependent Wnt activation, not the ligand-independent activation seen with APC or CTNNB1 mutations.
• Penetrance is uncertain and probably lower than the early family reports implied. RNF43 variants occur in people without serrated polyposis. At least one cohort found no germline variants.
• I found no pediatric presentation. Everything I retrieved concerns adults. The only age I have is a healthy 32-year-old carrier in the Danish series.

1. Disease information

Identifiers (database; GenCC submission by ClinGen, thegencc.org): - Disease title: "Sessile serrated polyposis cancer syndrome (OMIM:617108)" - MONDO:0014919 - MOI: autosomal dominant (HP:0000006) - Classification: Definitive, evaluated 12/30/2022

KEGG H02795 and MedGen C4310714 also index the disease (search results only, not opened). I did not check Orphanet, ICD-10/11 or MeSH, and I did not read OMIM or MONDO directly.

ClinGen notes, as returned by GenCC: - The gene was first linked to the syndrome in 2014 (Gala et al., PMID 24512911). - Seven variants (missense, nonsense, frameshift, splice site) in nine probands across seven publications were scored. - The proposed mechanism is heterozygous loss of function. - Experimental evidence from animal models, expression studies and in vitro assays supports the association.

Lump/split. SSPCS is the RNF43-defined subset of serrated polyposis syndrome (SPS). SPS is a clinical diagnosis by WHO criteria, and most SPS has no identified germline cause. I would keep SSPCS as a germline entry separate from the somatic serrated-pathway tumours. The source for this boundary is design-decisions §3a as cited in your instructions, not something I verified in this session.

Synonyms. The template lists SSPCS and RNF43-associated serrated polyposis. The OMIM wording appears in a LOVD record as "cancer, polyposis, sessile serrated syndrome (SSPCS)" (search result).

2. Etiology

• Cause. Heterozygous germline loss-of-function variants in RNF43. In the lesions examined, a somatic second hit inactivates the other allele. Yan et al. (Gut 2017;66:1645, DOI 10.1136/gutjnl-2016-311849; PMID not confirmed) found second-hit inactivation in "every serrated polyp, adenoma, and cancer examined" in one germline family (abstract via search summary).
• Genetic risk factors. I found no confirmed modifier genes. Gala et al. also reported senescence-pathway gene mutations (ATM, PIF1, TELO2, XAF1, RBL1) in 5 of 20 people with multiple sessile serrated adenomas (OR 3.0, 95% CI 0.9–8.9, P=.04). That is a separate, weak signal from a small cohort (primary, abstract only).
• Environmental risk factors for SPS in general. I did not search this. For this syndrome specifically I have no evidence, so I do not assert any.
• Protective factors and gene–environment interaction. Nothing found.

3. Phenotypes

Phenotype data come from a few small series, so frequencies are unavailable. The HPO terms below are suggestions I did not look up. Verify each CURIE with a lookup before binding.

• Onset and progression. I have no onset data beyond the single 32-year-old carrier. I found no quality-of-life data.
• Penetrance. The Danish paper states that "only three out of eight carriers (all relatives) had either serrated polyps or CRC." Only two members of one family met WHO SPS criteria. The authors conclude penetrance "is much lower than previously thought" (primary, PMID 39546056).
• Pediatric framing. Not established in what I retrieved. Before treating any minimum surveillance age as supported, check guidelines (ESGE, USMSTF, ACG), which I did not search.

4. Genetic and molecular information

• Variant spectrum.
• The Danish series (likely pathogenic under ACMG):
  • Exon 4–9 deletion, (c.375+1_376-1)_(2308+1_2309-1)del.
  • p.(Arg650Ter), c.1948C>T, in two families.
  • p.(Arg337Ter), c.1009C>T, in one family.
• Taupin et al. 2015: a nonsense variant in the extracellular domain in a severely affected kindred (Hum Genome Var 2:15013; the PMID 27081527 came from a search summary and is a lead).
• Gala et al. 2014: two probands with nonsense variants. The reported OR of 460 (95% CI 23.1–16384) has a very wide interval, so read it as a weak association.
• Conflicting cohorts.
• Buchanan et al., Gut 2017, a large multinational study, reported no evidence for germline RNF43 variants in SPS (title and finding from a search summary only; PMID unverified).
• A UK dataset study found RNF43 germline variants in CRC and polyp cases and also in controls, often without multiple polyps or notable family history (search result from the Oxford UK Biobank publication page, not read).
• Brinch et al. 2024 question whether RNF43 belongs on broad cancer panels, and call it speculative whether variants should instead be treated as "a contributing polygenetic risk factor" (primary).
• Somatic. RNF43 mutations were found in 34% of sporadic sessile and traditional serrated adenomas and 0% of hyperplastic polyps (Yan 2017, abstract). In MSI colorectal cancers, mutations were more frequent in the MLH1-methylated group (85%) than the unmethylated group (33.3%).
• Epigenetic. I did not research this. The MLH1 methylation association above comes from the somatic data only.

6. Mechanism (ordered chain)

1. A germline loss-of-function variant in RNF43 is inherited heterozygous. Truncating variants should trigger nonsense-mediated decay (predicted for Taupin's nonsense variant, per search summary).
2. In an intestinal epithelial cell, the second RNF43 allele is lost somatically. This is shown in a tumour-series from one family (Yan 2017), and I did not read ClinGen's wording on it.
3. RNF43 is a transmembrane E3 ubiquitin ligase. It normally ubiquitinates Frizzled and targets the receptor for degradation. Koo et al., Nature 2012 (DOI 10.1038/nature11308; PMID not confirmed) state: "RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation."
4. Without RNF43, Frizzled accumulates and the cell responds to Wnt ligand more strongly. Whether this is sufficient to start a serrated lesion is inferred, not demonstrated for SSPCS.
5. This leads to a sessile serrated lesion. The link between Wnt sensitisation and the serrated morphology is inferred from the somatic data, where RNF43 mutations are enriched in serrated lesions and absent from hyperplastic polyps.
6. Some lesions progress to MSI-high colorectal cancer. The MLH1-methylation association is correlative.

Branch. Gala et al. also proposed a role for RNF43 in the ATM–ATR DNA damage response, from knockdown in pancreatic duct cells (abstract only). I treat that as a second, less supported mechanism.

Mouse and cell models. - Koo 2012: simultaneous deletion of Rnf43 and Znrf3 in mouse intestinal epithelium induces "rapidly growing adenomas." This is a double knockout, so it does not model the human single-gene syndrome. The paper reports adenomas, not serrated lesions, so the model captures the Wnt mechanism but not the serrated phenotype. - R-spondin binds ZNRF3 and recruits LGR4, which clears ZNRF3 from the membrane (PMID 22575959, from a search URL, abstract not read). RSPO fusions and RNF43 loss therefore have a similar effect. - Jiang et al., PNAS 2013 (PMID unverified): in 39 pancreatic cancer lines, all LGK974-sensitive lines carried inactivating RNF43 mutations. A review notes the RNF43 R519X variant remained unaffected by PORCN inhibitors.

Suggested ontology terms (from memory, not looked up): GO "negative regulation of Wnt signaling pathway"; GO protein ubiquitination; CL intestinal crypt stem cell of colon (find the exact CURIE); UBERON colon, with emphasis on the proximal colon.

7. Anatomical structures

The colon is the primary organ, and the proximal colon is where WHO criteria place the lesions ("proximal to the sigmoid colon," per the search summary). Stomach involvement was seen in one carrier (gastric cancer at 61). Rectal and extracolonic involvement are not characterised.

8–9. Temporal development, inheritance, population

• Inheritance. Autosomal dominant, per ClinGen. Penetrance is low and variable, per the Danish series.
• Founder effects. I found none, though p.(Arg650Ter) in two Danish families may be worth checking against gnomAD (not done).
• Prevalence. Not found. Sex ratio, geography and anticipation are not found.

10–13. Diagnostics, outcome, treatment, prevention

• Diagnosis. SPS is diagnosed clinically by WHO criteria; the search summary quotes at least 5 sessile serrated polyps proximal to the sigmoid colon, 2 or more larger than 10 mm. Genetic testing uses multigene panels, and the Danish authors say existing guidelines differ on whether to include RNF43. Brinch 2024 recommends basing surveillance "on patient phenotype and clinical SPS criteria rather than genetic results alone."
• Prognosis. I found no survival or CRC risk estimates for RNF43 carriers. I did not search outcome data.
• Treatment. I did not search guidelines. Standard SPS management is colonoscopic polypectomy with surveillance and surgery in selected cases, but I did not verify that here. No RNF43-directed therapy is established for this syndrome. PORCN inhibitors are preclinical or trial-stage for RNF43-mutant tumours (review summary, not read). I found no NCT identifiers.
• Prevention. Cascade testing and colonoscopy surveillance are plausible, but the supporting guidance was not retrieved. The Danish authors' point that a variant alone does not establish high risk bears directly on counselling.

14–15. Other species and models

I did not search OMIA, MGI or ZFIN. The Rnf43/Znrf3 double knockout above is the only model I found. For single Rnf43 knockouts, the zebrafish record in the search results (ZFIN ZDB-PUB-120727-41) was not read.

Gaps and checks before curation

1. Unverified PMIDs. Koo 2012, Yan 2017, Buchanan 2017 and Jiang 2013 were not confirmed. Taupin 2015 came from a search summary. Only PMIDs 24512911 and 39546056 were confirmed by a retrieved source, and PMID 22575959 appears only in a search URL.
2. Unread papers. I could not open the PMC page for PMC8048817 (a reCAPTCHA page was returned). The Springer, UK Biobank and Buchanan items are abstract-level only, so I have no exact quotes from them.
3. Not searched. Orphanet, ClinVar, gnomAD, guidelines, HPO term lookup, GO/CL lookup, MGI/OMIA, and ClinicalTrials.gov.
4. ClinGen caveat. Definitive is a copied tier. The Danish 2024 paper postdates the 2022 evaluation, so a re-evaluation is plausible. I found no indication that ClinGen has changed the tier.

Sources

• GenCC/ClinGen submission
• Brinch et al. 2024, Familial Cancer
• Gala et al. 2014, PMC3978775
• Taupin et al. 2015, PMC4785559
• Yan et al. 2017, Gut
• Koo et al. 2012, Nature
• ZNRF3 R-spondin, PMID 22575959
• Jiang et al. 2013, PMC3732970

Reference Validation

Checked with linkml-reference-validator 0.4.0.

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

• PMID:22575959 (5 mentions) - ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner.
• shared terms: rnf43

Weighed against this report's own most characteristic terms: found, rnf43, serrated, cancer, clingen, danish, sessile, variant, read, polyp, sps, family, germline, primary, syndrome, gala, unverified, yan, colon, polyposis.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0000006 (1 mention) - the report calls it "MOI: autosomal dominant"; HP calls it Autosomal dominant inheritance, and lists "Autosomal dominant" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM.

4 of 6 terms resolved to a current term; the rest could not be looked up either way.