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Mappings

MONDO

MONDO:0014919 sessile serrated polyposis cancer syndrome

Primary MONDO identifier. MONDO defines this term by germline RNF43 variants (OMIM:617108 cross-reference) and places it as a child of the clinically defined hyperplastic polyposis syndrome.

MONDO:0015524 hyperplastic polyposis syndrome Not Yet Curated

MONDO parent term for the clinically defined serrated polyposis syndrome (WHO endoscopic criteria, any or no germline cause). This entry covers only the RNF43-defined child; the clinical syndrome is broader and remains uncurated, so the mapping is broadMatch and does not retire the parent from the curation queue.

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Inheritance

1

Autosomal dominant with incomplete penetrance HP:0000006

Heterozygous germline RNF43 loss-of-function variants cosegregate with serrated polyposis in an autosomal dominant pattern in the reported kindreds. Penetrance is incomplete and probably lower than the family-based literature implied: carriers ascertained outside polyposis families often lack polyps, and colorectal cancer risk depends on where the truncation falls in the protein. No numeric penetrance estimate is recorded because none of the cited sources provides one.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (4 references)

PMID:27329244 SUPPORT Human clinical

"In one out of four serrated polyposis families, we identified a germline RNF43 mutation that displayed autosomal dominant cosegregation with the serrated polyposis phenotype"

Family study showing dominant cosegregation of a germline RNF43 variant with serrated polyposis.

CGGV:assertion_9abf2a1d-21a7-4ef7-99c7-b0b37d5acf38-2022-12-30T180000.000Z SUPPORT Other

ClinGen records the mode of inheritance for this gene-disease pair as autosomal dominant.

PMID:39546056 SUPPORT Human clinical

"Our findings suggest that the penetrance of RNF43-related disease is much lower than previously thought, and raise questions about the connection between RNF43 and disease."

Four Danish families with likely pathogenic RNF43 variants, three without serrated polyps or colorectal cancer, support incomplete penetrance.

+ 1 more reference

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Discussions and Knowledge Gaps

2

How much of clinically defined serrated polyposis syndrome does germline RNF43 explain, and is the RNF43-defined entity a subtype of SPS or a separate predisposition that sometimes presents as SPS?

KNOWLEDGE GAP rnf43_yield_in_clinical_sps

Attached to

disease#Sessile Serrated Polyposis Cancer Syndrome genetic#RNF43

MONDO places the RNF43-defined term under the clinical syndrome, but cohort yields of RNF43 in WHO-criteria SPS are low (none of 26 in a Dutch cohort, 1 of 73 and 1 of 139 in two UK series, 5 of 304 in a multinational study cited as background), and a review puts all identifiable germline causes below 3%. In the other direction, population carriers often lack polyposis. The overlap between the two concepts is therefore partial in both directions, which is why this entry follows the MONDO split rather than lumping clinical SPS into it. Whether the residual clinical SPS has an undiscovered Mendelian cause, a polygenic or environmental basis (smoking is associated), or both, is open.

Show evidence (3 references)

PMID:33098683 SUPPORT BACKGROUND Human clinical

"a large multinational cohort found five of 304 (1.6%) tested SPS patients with probably pathogenic RNF43 variants."

Background citation of a multinational yield. The primary letters this sentence cites have no abstract in the reference cache, so the figure could not be checked against them; one of them (Buchanan et al., Gut 2017) is titled as reporting a lack of evidence for germline RNF43 variants in SPS, which shows how contested the yield is.

PMID:31673925 SUPPORT REVIEW SYNTHESIS Other

"However, less than 3% of serrated polyposis syndrome cases are explained by identifiable germline mutations, with mutations in RNF43 being the only currently validated genetic cause."

Review estimate of the germline-explained fraction of SPS.

PMID:35988960 SUPPORT REVIEW SYNTHESIS Other

"Besides a small proportion of cases caused by germline mutations in RNF43, no clear genetic cause has been identified."

Review stating that RNF43 explains only a small proportion of SPS.

What is the age-specific penetrance of germline RNF43 variants by variant position, and at what age should surveillance of an asymptomatic carrier (including a carrier identified as a child through cascade testing) begin?

KNOWLEDGE GAP rnf43_penetrance_and_surveillance_start

Attached to

inheritance#Autosomal dominant with incomplete penetrance treatments#Colonoscopic Surveillance with Polypectomy

The family-based literature suggested a high-risk dominant syndrome, with colorectal cancer as early as age 23, but population sequencing shows a moderate overall risk concentrated in N-terminal variants, and Danish families include older carriers with normal colonoscopy. None of the sources cited in this entry gives an age to start colonoscopy in RNF43 carriers or addresses predictive testing of minors; the surveillance data come from adults with clinical SPS. This matters for pediatric cascade testing, because the case for testing a child depends on a surveillance action taken in childhood or early adulthood.

Show evidence (2 references)

PMID:41443981 SUPPORT Human clinical

"In case-control analyses, germline RNF43 variants were associated with CRC risk (OR=2.696, p=0.010), but penetrance was much greater for germline mutations in the N-terminal half of the gene."

Position-dependent risk without age-specific penetrance.

PMID:39546056 SUPPORT Human clinical

"This highlights the complexity of genetic counseling in RNF43 positive families, and whether healthy relatives should be offered predictive testing."

States that predictive testing of healthy relatives is unresolved.

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Pathophysiology

5

Germline Heterozygous RNF43 Loss of Function

A heterozygous germline truncating (nonsense, frameshift) or other loss-of-function RNF43 variant is present in every cell and constitutes the first hit. RNF43 encodes a transmembrane RING-type E3 ubiquitin ligase, so the constitutional defect is a halving of a negative regulator of Wnt receptor abundance. ClinGen records heterozygous loss of function as the reported mechanism.

RNF43 hgnc:18505 ↓ DECREASED

Genetic context RNF43 hgnc:18505 variant_origin: GERMLINE allelic_hit_role: FIRST_HIT allelic_event: NONSENSE_VARIANT allelic_event: FRAMESHIFT_VARIANT allelic_event: PATHOGENIC_VARIANT zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous germline RNF43 loss-of-function variants; the reported kindreds carry nonsense or frameshift alleles.

E3 ubiquitin ligase activity of RNF43 GO:0004842 ↓ DECREASED

Downstream

Somatic Second-Hit Inactivation of RNF43 in Colorectal Polyps Polyps arise from cells that lose the remaining wild-type RNF43 allele.

Show evidence (3 references)

PMID:27081527 SUPPORT Human clinical

"We report a germline nonsense mutation within the extracellular domain of the RING finger ubiquitin ligase RNF43, segregating with a severe form of serrated polyposis within a kindred."

Kindred study identifying a germline RNF43 nonsense allele segregating with serrated polyposis.

PMID:24512911 SUPPORT Human clinical

"In 2 subjects,we found nonsense mutations in RNF43, indicating that it is also associated with multiple serrated polyps"

The first report of germline RNF43 nonsense variants, found in 2 of 20 exome-sequenced individuals with multiple sessile serrated adenomas.

CGGV:assertion_9abf2a1d-21a7-4ef7-99c7-b0b37d5acf38-2022-12-30T180000.000Z SUPPORT Other

"The mechanism of pathogenicity is reported to be heterozygous LOF."

ClinGen's evidence summary states heterozygous loss of function as the disease mechanism.

Somatic Second-Hit Inactivation of RNF43 in Colorectal Polyps

In the one germline-carrier family studied at the lesion level, all 16 serrated polyps, 5 adenomas and 1 cancer examined showed second-hit inactivation of RNF43 by loss of heterozygosity or a somatic mutation. The second hit has not been examined in most other reported kindreds (the Australian kindred report states it was not determined), so its generality is inferred from this one family and from RNF43's tumour-suppressor behaviour in sporadic tumours.

RNF43 hgnc:18505 ↓ DECREASED

Genetic context RNF43 hgnc:18505 variant_origin: SOMATIC allelic_hit_role: SECOND_HIT allelic_event: LOSS_OF_HETEROZYGOSITY allelic_event: PATHOGENIC_VARIANT functional_impact_category: LOSS_OF_FUNCTION

Somatic loss of the wild-type RNF43 allele in polyps of a germline carrier, by loss of heterozygosity or a second somatic mutation.

E3 ubiquitin ligase activity of RNF43 GO:0004842 ↓ DECREASED

Downstream

Impaired Frizzled Ubiquitination and Wnt Receptor Turnover Biallelic loss of RNF43 removes its E3 ligase activity toward Frizzled receptors in the affected crypt.

Show evidence (2 references)

PMID:27329244 SUPPORT Human clinical

"along with second-hit inactivation through loss of heterozygosity or somatic mutations in all serrated polyps (16), adenomas (5) and cancer (1) examined"

Direct lesion-level demonstration of the second hit in polyps and cancer of a germline RNF43 carrier family.

PMID:27081527 NO_EVIDENCE Human clinical

"As a candidate tumor suppressor gene, RNF43 may be subject to allelic loss or somatic inactivation of the wild-type allele, which is a question for further scrutiny."

Recorded to show that the second hit was not tested in this kindred; it neither supports nor refutes the claim.

Impaired Frizzled Ubiquitination and Wnt Receptor Turnover

RNF43 and its homologue ZNRF3 ubiquitinate Frizzled receptors and route them to lysosomal degradation, keeping Wnt receptor levels low. Without RNF43, Frizzled receptors persist at the cell surface. This node is supported by cell-line and mouse work rather than by measurements in carriers' tissue.

Frizzled receptor degradation GO:0038018 ↓ DECREASED

Downstream

Increased Wnt Signalling with Reduced R-spondin Dependence Persisting Frizzled receptors raise Wnt responsiveness of the epithelium.

Show evidence (2 references)

PMID:22895187 SUPPORT In vitro / ex vivo

"In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes."

Cell-line evidence that RNF43 drives Frizzled receptor removal, the activity lost in this disease.

PMID:22895187 SUPPORT In vitro / ex vivo

"We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation."

The authors' mechanistic conclusion: RNF43 ubiquitinates Frizzled for degradation.

Increased Wnt Signalling with Reduced R-spondin Dependence

Loss of RNF43 raises canonical Wnt signalling in intestinal stem cells and makes epithelial growth less dependent on the Wnt agonist R-spondin. Combined deletion of Rnf43 and Znrf3 in mouse intestinal epithelium produces adenomas rich in LGR5+ stem cells, and RNF43-mutant human serrated adenoma organoids and edited mouse colon organoids grow with less R-spondin1. How this Wnt gain leads specifically to serrated rather than conventional adenomatous morphology in human carriers is not established.

LGR5+ intestinal crypt stem cell CL:0002250

canonical Wnt signaling GO:0060070 ↑ INCREASED

Downstream

Serrated Colorectal Polyps Wnt gain in RNF43-null crypts contributes to serrated polyp formation; the intermediate steps in human colon are not defined.

Show evidence (3 references)

PMID:22895187 SUPPORT Model organism

"Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5+ stem cells."

Places RNF43 in the intestinal crypt stem cell, the cell type bound on this node (mouse data).

PMID:22895187 SUPPORT Model organism

"Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5+ stem cells."

In vivo consequence of losing RNF43 and ZNRF3 together in intestinal epithelium. It is a double-knockout, so it overstates the effect of RNF43 loss alone.

PMID:27329244 SUPPORT In vitro / ex vivo

"Functionally, organoid culture of serrated adenoma or mouse colon with CRISPR-induced RNF43 mutations had reduced dependency on R-spondin1."

Organoid evidence that RNF43 loss lowers dependence on the Wnt agonist R-spondin1.

Somatic BRAF Activation in Carrier Polyps

In the germline RNF43 carrier family studied at the lesion level, 62.5% of serrated polyps also carried a somatic BRAF mutation, consistent with the serrated neoplasia pathway in which BRAF (or less often KRAS) mutation is an early somatic event. BRAF activation is recorded here as a cooperating somatic event in carriers' polyps, not as part of the germline mechanism. The downstream serrated-pathway tumour biology (CIMP, MLH1 promoter methylation, BRAF V600E-mutant carcinoma) is curated in the somatic tumour entries.

BRAF hgnc:1097 ↑ INCREASED

Genetic context BRAF hgnc:1097 variant_origin: SOMATIC allelic_hit_role: COOPERATING_HIT allelic_event: MISSENSE_VARIANT functional_impact_category: GAIN_OF_FUNCTION

Somatic BRAF mutation co-occurring with RNF43 second hits in carriers' serrated polyps.

Downstream

Serrated Colorectal Polyps Somatic BRAF activation cooperates with RNF43 loss in serrated polyp formation.

Show evidence (2 references)

PMID:27329244 SUPPORT Human clinical

"as well as coincidental BRAF mutation in 62.5% of the serrated polyps"

Measured frequency of somatic BRAF mutation in the serrated polyps of the germline RNF43 carrier family.

PMID:24512911 SUPPORT BACKGROUND Human clinical

"SSAs contain somatic mutations in BRAF or KRAS early in development."

Background statement that BRAF or KRAS mutation is an early somatic event in sessile serrated adenomas generally.

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Pathograph

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Phenotypes

2

Serrated Colorectal Polyps Gastrointestinal HP:0032222

Sequelae: Colorectal Carcinoma

Show evidence (2 references)

PMID:27081527 SUPPORT Human clinical

"The proband developed microsatellite instability (MSI)– CRC age 23 years arising from a serrated polyp, in the setting of multiple (>50) large serrated polyps throughout the colon"

More than 50 large serrated polyps in a germline RNF43 carrier.

PMID:39546056 SUPPORT Human clinical

"Colonoscopies in the probands of these families did not reveal any serrated polyps and/or CRC despite some of them being relatively old."

Shows the phenotype is absent in some carriers, so no frequency is recorded.

Colorectal Carcinoma Neoplastic HP:0003003

Show evidence (2 references)

PMID:27081527 SUPPORT Human clinical

"The proband developed microsatellite instability (MSI)– CRC age 23 years arising from a serrated polyp, in the setting of multiple (>50) large serrated polyps throughout the colon"

Early-onset colorectal cancer arising from a serrated polyp in a germline RNF43 carrier.

PMID:41443981 SUPPORT Human clinical

"RNF43 is a CRC predisposition gene, but risks are moderate, the reported polyposis phenotype is often absent and molecular phenocopies can occur."

Supports colorectal cancer as a phenotype while bounding the risk as moderate.

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Genetic Associations

1

RNF43

Gene: RNF43 hgnc:18505 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:41443981 SUPPORT Human clinical

"Germline C-terminal mutations conferred no increased CRC risk."

Genotype-phenotype result: risk is confined to N-terminal variants in this case-control analysis.

PMID:41443981 SUPPORT Human clinical

"However, while 23 CRC/polyp cases and 47 controls from 100kGP or UKB had germline RNF43 mutations, cases often lacked multiple polyps or a notable family history."

Germline RNF43 variants occur in unselected controls and in cases without polyposis, so carriage alone does not establish the syndrome.

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Medical Actions

3

Colonoscopic Surveillance with Polypectomy

Action: colonoscopic polypectomy Ontology label: Colonoscopic Polypectomy NCIT:C51688

Regular colonoscopy with removal of serrated and adenomatous polyps. The surveillance data come from clinically defined SPS cohorts, not from RNF43 carriers specifically. In those cohorts advanced neoplasia is common during surveillance while colorectal cancer incidence is low, and a randomized trial could not show that a 3-year interval is non-inferior to a 2-year interval. For RNF43 carriers, the source recommends individually tailored colonoscopy taking account of variant position and polyp history.

Mechanism Target:

INHIBITS Serrated Colorectal Polyps — Removes polyps before they progress; does not correct the germline defect.

Show evidence (3 references)

PMID:30068004 SUPPORT Human clinical

"Patients with SPS have a substantial risk of developing advanced neoplasia under endoscopic surveillance, whereas CRC incidence is low."

Multicentre SPS surveillance cohort (not genotyped for RNF43) supporting surveillance with polyp removal.

PMID:42012787 SUPPORT Human clinical

"In patients with serrated polyposis syndrome, extending colonoscopy surveillance to a three-year compared with a two-year interval yielded inconclusive evidence regarding non-inferiority for advanced neoplasia incidence."

Randomized trial in WHO-criteria SPS; the surveillance interval is not settled.

PMID:41443981 SUPPORT Human clinical

"Our data do, however, suggest that once a germline RNF43 variant has been identified, a pragmatic screening approach is required, for example managing patients individually by regular colonoscopy, tailored to the position of the germline variant, polyp formation and progression over time."

RNF43-specific management suggestion from the authors of the largest carrier study.

Colectomy for Unmanageable Polyp Burden or Cancer

Action: colectomy Ontology label: Colectomy NCIT:C15209

Platform: Surgery

(Sub)total colectomy is used when polyp burden cannot be controlled endoscopically or cancer develops; endoscopic surveillance of the remaining rectum or sigmoid continues afterwards. Data are from clinically defined SPS, not RNF43 carriers specifically.

Mechanism Target:

INHIBITS Colorectal Carcinoma — Removes the at-risk colon.

Show evidence (2 references)

PMID:31403493 SUPPORT Human clinical

"(Sub)total colectomy mitigates much of the excess risk of CRC in patients with SPS."

Prospective cohort of 48 SPS patients after colectomy with no colorectal cancer during follow-up.

PMID:30068004 SUPPORT Human clinical

"After total colectomy, 17.9 % patients developed advanced neoplasia in the retained rectum."

Supports continued rectal surveillance after colectomy.

Genetic Counseling and Cascade Testing

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic counseling for individuals with SPS and their relatives, and cascade testing of relatives once an RNF43 variant is found. Because penetrance is incomplete, counseling of carriers without polyposis is difficult and the value of predictive testing in healthy relatives is not settled.

Show evidence (2 references)

PMID:31673925 SUPPORT REVIEW SYNTHESIS Other

"Referral for genetic counseling and testing is recommended for individuals with serrated polyposis syndrome and a personal history of coexisting adenomatous polyposis or with a concerning family history and can be considered for all individuals with serrated polyposis syndrome."

Review recommendation on when to refer for genetic counseling.

PMID:39546056 SUPPORT Human clinical

"This highlights the complexity of genetic counseling in RNF43 positive families, and whether healthy relatives should be offered predictive testing."

Danish family series raising the unresolved question of predictive testing in relatives.

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Diagnosis

2

Clinical diagnosis of serrated polyposis by WHO 2019 criteria

The clinical syndrome is diagnosed endoscopically by cumulative serrated polyp count, size and location under the WHO 2019 criteria (at least 5 serrated lesions proximal to the rectum, all at least 5 mm and at least 2 of 10 mm or more; or more than 20 serrated lesions throughout the colon with at least 5 proximal to the rectum). These criteria define clinical SPS, not this RNF43-defined entry: a carrier may not meet them.

colonoscopy NCIT:C16450

Show evidence (2 references)

PMID:41002021 SUPPORT BACKGROUND Human clinical

"(i) ≥5 serrated lesions/polyps proximal to the rectum all being ≥5 mm in size, with ≥2 being ≥10 mm in size or (ii) >20 serrated lesions/polyps of any size distributed throughout the large bowel, with ≥5 being proximal to the rectum"

States the WHO 2019 diagnostic criteria in the paper's introduction.

PMID:35988960 SUPPORT REVIEW SYNTHESIS Other

"Both epigenetic and environmental factors, especially smoking, have been related to this syndrome, but the etiology of SPS remains uncertain and diagnosis is based on endoscopic criteria."

Review stating that SPS diagnosis rests on endoscopic criteria and that non-genetic factors contribute.

Germline multigene panel testing including RNF43

Germline testing of a multigene colorectal cancer and polyposis panel that includes RNF43 identifies this entry. The yield of an RNF43 variant in clinically defined SPS is low: 1 of 139 panel-tested patients in a UK registry, 1 of 73 tested patients in a second UK series, and none of 26 in a Dutch cohort. Panel testing in SPS also detects other syndromes, notably Lynch syndrome and MUTYH-associated polyposis.

germline genetic testing NCIT:C15709

Show evidence (3 references)

PMID:41002021 SUPPORT Human clinical

"On multigene panel testing, pathogenic germline variants were found in 4 patients (2.9%), including 3 with Lynch syndrome (2 with PMS2 , one with MSH2 ) and one with an RNF43 variant."

One RNF43 variant among 139 panel-tested WHO-criteria SPS patients at St Mark's Hospital.

PMID:35128723 SUPPORT Human clinical

"Seventy-three patients underwent genetic testing and 15/73 (20.5%) were found to have germline variants, of which 7/73 (9.6%) had a pathogenic variant (MUTYH n = 2, SMAD4 n = 1, CHEK2 n = 2, POLD1 n = 1, and RNF43 n = 1)."

One RNF43 pathogenic variant among 73 tested SPS patients in Oxford.

PMID:33098683 SUPPORT Human clinical

"No germline RNF43 pathogenic variants were detected in our SPS cohort."

No RNF43 pathogenic variants in 26 SPS patients sequenced for all RNF43 exons.

{ }

Source YAML

click to show

name: Sessile Serrated Polyposis Cancer Syndrome
creation_date: "2026-10-26T00:00:00Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Gastrointestinal Neoplasia
parents:
- hyperplastic polyposis syndrome
- hereditary cancer-predisposing syndrome
disease_term:
  preferred_term: sessile serrated polyposis cancer syndrome
  term:
    id: MONDO:0014919
    label: sessile serrated polyposis cancer syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014919
      label: sessile serrated polyposis cancer syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier. MONDO defines this term by germline RNF43 variants
      (OMIM:617108 cross-reference) and places it as a child of the clinically defined
      hyperplastic polyposis syndrome.
  - term:
      id: MONDO:0015524
      label: hyperplastic polyposis syndrome
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO parent term for the clinically defined serrated polyposis syndrome (WHO
      endoscopic criteria, any or no germline cause). This entry covers only the
      RNF43-defined child; the clinical syndrome is broader and remains uncurated, so
      the mapping is broadMatch and does not retire the parent from the curation queue.
synonyms:
- SSPCS
- RNF43-associated serrated polyposis
- RNF43-related serrated polyposis
description: >-
  Sessile serrated polyposis cancer syndrome (SSPCS) is the germline,
  RNF43-defined form of serrated polyposis: an autosomal dominant predisposition
  to multiple serrated colorectal polyps and colorectal cancer caused by
  heterozygous loss-of-function variants in RNF43, a transmembrane E3 ubiquitin
  ligase that restrains Wnt signalling by ubiquitinating Frizzled receptors and
  targeting them for degradation. ClinGen classifies the RNF43-SSPCS relationship
  as Definitive (autosomal dominant). This entry is deliberately narrower than
  the clinical serrated polyposis syndrome (SPS), which is defined by WHO
  endoscopic criteria regardless of cause; RNF43 explains only a small minority of
  clinically defined SPS (0 to about 2% of tested cohorts in the series cited
  here), and the clinical syndrome is linked to smoking and other non-Mendelian
  factors. Conversely, population-based sequencing shows that many germline RNF43
  carriers have neither polyposis nor a notable family history, that colorectal
  cancer risk is moderate overall, and that risk is concentrated in N-terminal
  truncating variants. Mechanistically the entry is a germline two-hit
  predisposition: the polyps of carriers show second-hit RNF43 inactivation and
  frequent somatic BRAF mutation, placing them on the serrated neoplasia pathway.
  The somatic serrated-pathway colorectal cancers this syndrome predisposes to
  (for example BRAF V600E-mutant, CIMP-high colorectal cancer) are curated as
  separate entries and are not merged here.
notes: >-
  Lump/split. MONDO splits the RNF43-defined term (MONDO:0014919, OMIM:617108)
  from the clinically defined hyperplastic polyposis syndrome (MONDO:0015524,
  ORPHA:157798). This entry follows that split and curates the gene-defined
  child only. Clinical SPS without an RNF43 variant is not described by this
  entry's pathophysiology, and an RNF43 carrier who does not meet WHO criteria is
  still within this entry's genotype definition but may have no polyposis at all
  (see the discussions). The serrated pathway's somatic events (BRAF activation,
  CIMP, MLH1 promoter methylation) belong to the tumor entries such as
  BRAF_V600E_Mutant_Colorectal_Cancer; only the somatic BRAF mutation observed
  in carriers' polyps is recorded here, because it was measured in germline
  carriers.
inheritance:
- name: Autosomal dominant with incomplete penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Heterozygous germline RNF43 loss-of-function variants cosegregate with
    serrated polyposis in an autosomal dominant pattern in the reported kindreds.
    Penetrance is incomplete and probably lower than the family-based literature
    implied: carriers ascertained outside polyposis families often lack polyps,
    and colorectal cancer risk depends on where the truncation falls in the
    protein. No numeric penetrance estimate is recorded because none of the
    cited sources provides one.
  evidence:
  - reference: PMID:27329244
    reference_title: "RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In one out of four serrated polyposis families, we identified a germline
      RNF43 mutation that displayed autosomal dominant cosegregation with the
      serrated polyposis phenotype
    explanation: >-
      Family study showing dominant cosegregation of a germline RNF43 variant
      with serrated polyposis.
  - reference: CGGV:assertion_9abf2a1d-21a7-4ef7-99c7-b0b37d5acf38-2022-12-30T180000.000Z
    reference_title: "RNF43 / sessile serrated polyposis cancer syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RNF43 | HGNC:18505 | sessile serrated polyposis cancer syndrome | MONDO:0014919 | AD | Definitive"
    explanation: >-
      ClinGen records the mode of inheritance for this gene-disease pair as
      autosomal dominant.
  - reference: PMID:39546056
    reference_title: "Germline pathogenic variants in RNF43 in patients with and without serrated polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that the penetrance of RNF43-related disease is much
      lower than previously thought, and raise questions about the connection
      between RNF43 and disease.
    explanation: >-
      Four Danish families with likely pathogenic RNF43 variants, three without
      serrated polyps or colorectal cancer, support incomplete penetrance.
  - reference: PMID:41443981
    reference_title: "Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In case-control analyses, germline RNF43 variants were associated with CRC
      risk (OR=2.696, p=0.010), but penetrance was much greater for germline
      mutations in the N-terminal half of the gene.
    explanation: >-
      Large case-control analysis (CORGI, 100,000 Genomes, UK Biobank) showing a
      moderate overall colorectal cancer risk and position-dependent penetrance.
pathophysiology:
- name: Germline Heterozygous RNF43 Loss of Function
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  description: >-
    A heterozygous germline truncating (nonsense, frameshift) or other
    loss-of-function RNF43 variant is present in every cell and constitutes the
    first hit. RNF43 encodes a transmembrane RING-type E3 ubiquitin ligase, so
    the constitutional defect is a halving of a negative regulator of Wnt
    receptor abundance. ClinGen records heterozygous loss of function as the
    reported mechanism.
  role: trigger
  biological_scale: MOLECULAR
  gene:
    preferred_term: RNF43
    modifier: DECREASED
    term:
      id: hgnc:18505
      label: RNF43
  genetic_context:
    gene:
      preferred_term: RNF43
      term:
        id: hgnc:18505
        label: RNF43
    variant_origin: GERMLINE
    allelic_hit_role: FIRST_HIT
    allelic_events:
    - NONSENSE_VARIANT
    - FRAMESHIFT_VARIANT
    - PATHOGENIC_VARIANT
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous germline RNF43 loss-of-function variants; the reported
      kindreds carry nonsense or frameshift alleles.
  molecular_functions:
  - preferred_term: E3 ubiquitin ligase activity of RNF43
    term:
      id: GO:0004842
      label: ubiquitin-protein transferase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:27081527
    reference_title: "A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a germline nonsense mutation within the extracellular domain of
      the RING finger ubiquitin ligase RNF43, segregating with a severe form of
      serrated polyposis within a kindred.
    explanation: >-
      Kindred study identifying a germline RNF43 nonsense allele segregating with
      serrated polyposis.
  - reference: PMID:24512911
    reference_title: "Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 2 subjects,we found nonsense mutations in RNF43, indicating that it is
      also associated with multiple serrated polyps
    explanation: >-
      The first report of germline RNF43 nonsense variants, found in 2 of 20
      exome-sequenced individuals with multiple sessile serrated adenomas.
  - reference: CGGV:assertion_9abf2a1d-21a7-4ef7-99c7-b0b37d5acf38-2022-12-30T180000.000Z
    reference_title: "RNF43 / sessile serrated polyposis cancer syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is reported to be heterozygous LOF."
    explanation: >-
      ClinGen's evidence summary states heterozygous loss of function as the
      disease mechanism.
  downstream:
  - target: Somatic Second-Hit Inactivation of RNF43 in Colorectal Polyps
    description: >-
      Polyps arise from cells that lose the remaining wild-type RNF43 allele.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27329244
      reference_title: "RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        along with second-hit inactivation through loss of heterozygosity or
        somatic mutations in all serrated polyps (16), adenomas (5) and cancer
        (1) examined
      explanation: >-
        In the germline-carrier family, every lesion examined had lost or
        mutated the second RNF43 allele.
- name: Somatic Second-Hit Inactivation of RNF43 in Colorectal Polyps
  conforms_to: "germline_two_hit_tumor_predisposition#Somatic Second-Hit Inactivation of the Wild-Type Allele"
  description: >-
    In the one germline-carrier family studied at the lesion level, all 16
    serrated polyps, 5 adenomas and 1 cancer examined showed second-hit
    inactivation of RNF43 by loss of heterozygosity or a somatic mutation. The
    second hit has not been examined in most other reported kindreds (the
    Australian kindred report states it was not determined), so its generality is
    inferred from this one family and from RNF43's tumour-suppressor behaviour in
    sporadic tumours.
  role: effector
  biological_scale: MOLECULAR
  gene:
    preferred_term: RNF43
    modifier: DECREASED
    term:
      id: hgnc:18505
      label: RNF43
  genetic_context:
    gene:
      preferred_term: RNF43
      term:
        id: hgnc:18505
        label: RNF43
    variant_origin: SOMATIC
    allelic_hit_role: SECOND_HIT
    allelic_events:
    - LOSS_OF_HETEROZYGOSITY
    - PATHOGENIC_VARIANT
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Somatic loss of the wild-type RNF43 allele in polyps of a germline
      carrier, by loss of heterozygosity or a second somatic mutation.
  molecular_functions:
  - preferred_term: E3 ubiquitin ligase activity of RNF43
    term:
      id: GO:0004842
      label: ubiquitin-protein transferase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:27329244
    reference_title: "RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      along with second-hit inactivation through loss of heterozygosity or
      somatic mutations in all serrated polyps (16), adenomas (5) and cancer
      (1) examined
    explanation: >-
      Direct lesion-level demonstration of the second hit in polyps and cancer
      of a germline RNF43 carrier family.
  - reference: PMID:27081527
    reference_title: "A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As a candidate tumor suppressor gene, RNF43 may be subject to allelic loss
      or somatic inactivation of the wild-type allele, which is a question for
      further scrutiny.
    explanation: >-
      Recorded to show that the second hit was not tested in this kindred; it
      neither supports nor refutes the claim.
  downstream:
  - target: Impaired Frizzled Ubiquitination and Wnt Receptor Turnover
    description: >-
      Biallelic loss of RNF43 removes its E3 ligase activity toward Frizzled
      receptors in the affected crypt.
    causal_link_type: DIRECT
- name: Impaired Frizzled Ubiquitination and Wnt Receptor Turnover
  description: >-
    RNF43 and its homologue ZNRF3 ubiquitinate Frizzled receptors and route them
    to lysosomal degradation, keeping Wnt receptor levels low. Without RNF43,
    Frizzled receptors persist at the cell surface. This node is supported by
    cell-line and mouse work rather than by measurements in carriers' tissue.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Frizzled receptor degradation
    term:
      id: GO:0038018
      label: Wnt receptor catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:22895187
    reference_title: "Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt
      responses and targets surface-expressed frizzled receptors to lysosomes.
    explanation: >-
      Cell-line evidence that RNF43 drives Frizzled receptor removal, the
      activity lost in this disease.
  - reference: PMID:22895187
    reference_title: "Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively
      ubiquitinating frizzled receptors, thereby targeting these Wnt receptors
      for degradation.
    explanation: >-
      The authors' mechanistic conclusion: RNF43 ubiquitinates Frizzled for
      degradation.
  downstream:
  - target: Increased Wnt Signalling with Reduced R-spondin Dependence
    description: >-
      Persisting Frizzled receptors raise Wnt responsiveness of the epithelium.
    causal_link_type: DIRECT
- name: Increased Wnt Signalling with Reduced R-spondin Dependence
  description: >-
    Loss of RNF43 raises canonical Wnt signalling in intestinal stem cells and
    makes epithelial growth less dependent on the Wnt agonist R-spondin.
    Combined deletion of Rnf43 and Znrf3 in mouse intestinal epithelium produces
    adenomas rich in LGR5+ stem cells, and RNF43-mutant human serrated adenoma
    organoids and edited mouse colon organoids grow with less R-spondin1. How
    this Wnt gain leads specifically to serrated rather than conventional
    adenomatous morphology in human carriers is not established.
  role: central_effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: LGR5+ intestinal crypt stem cell
    term:
      id: CL:0002250
      label: intestinal crypt stem cell
  biological_processes:
  - preferred_term: canonical Wnt signaling
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:22895187
    reference_title: "Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin
      ligases are uniquely expressed in LGR5+ stem cells.
    explanation: >-
      Places RNF43 in the intestinal crypt stem cell, the cell type bound on this
      node (mouse data).
  - reference: PMID:22895187
    reference_title: "Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Simultaneous deletion of the two genes encoding these proteins in the
      intestinal epithelium of mice induces rapidly growing adenomas containing
      high numbers of Paneth and LGR5+ stem cells.
    explanation: >-
      In vivo consequence of losing RNF43 and ZNRF3 together in intestinal
      epithelium. It is a double-knockout, so it overstates the effect of RNF43
      loss alone.
  - reference: PMID:27329244
    reference_title: "RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functionally, organoid culture of serrated adenoma or mouse colon with
      CRISPR-induced RNF43 mutations had reduced dependency on R-spondin1.
    explanation: >-
      Organoid evidence that RNF43 loss lowers dependence on the Wnt agonist
      R-spondin1.
  downstream:
  - target: Serrated Colorectal Polyps
    description: >-
      Wnt gain in RNF43-null crypts contributes to serrated polyp formation; the
      intermediate steps in human colon are not defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Somatic BRAF Activation in Carrier Polyps
  description: >-
    In the germline RNF43 carrier family studied at the lesion level, 62.5% of
    serrated polyps also carried a somatic BRAF mutation, consistent with the
    serrated neoplasia pathway in which BRAF (or less often KRAS) mutation is an
    early somatic event. BRAF activation is recorded here as a cooperating
    somatic event in carriers' polyps, not as part of the germline mechanism.
    The downstream serrated-pathway tumour biology (CIMP, MLH1 promoter
    methylation, BRAF V600E-mutant carcinoma) is curated in the somatic tumour
    entries.
  role: modifier
  biological_scale: MOLECULAR
  gene:
    preferred_term: BRAF
    modifier: INCREASED
    term:
      id: hgnc:1097
      label: BRAF
  genetic_context:
    gene:
      preferred_term: BRAF
      term:
        id: hgnc:1097
        label: BRAF
    variant_origin: SOMATIC
    allelic_hit_role: COOPERATING_HIT
    allelic_events:
    - MISSENSE_VARIANT
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Somatic BRAF mutation co-occurring with RNF43 second hits in carriers'
      serrated polyps.
  evidence:
  - reference: PMID:27329244
    reference_title: "RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as well as coincidental BRAF mutation in 62.5% of the serrated polyps
    explanation: >-
      Measured frequency of somatic BRAF mutation in the serrated polyps of the
      germline RNF43 carrier family.
  - reference: PMID:24512911
    reference_title: "Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "SSAs contain somatic mutations in BRAF or KRAS early in development."
    explanation: >-
      Background statement that BRAF or KRAS mutation is an early somatic event
      in sessile serrated adenomas generally.
  downstream:
  - target: Serrated Colorectal Polyps
    description: >-
      Somatic BRAF activation cooperates with RNF43 loss in serrated polyp
      formation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Gastrointestinal
  name: Serrated Colorectal Polyps
  description: >-
    Multiple serrated colorectal polyps (sessile serrated lesions, traditional
    serrated adenomas, hyperplastic polyps), often large and proximal, in the
    reported kindreds. Not every carrier develops them.
  phenotype_term:
    preferred_term: Serrated colorectal polyps
    term:
      id: HP:0032222
      label: Serrated intestinal polyps
  evidence:
  - reference: PMID:27081527
    reference_title: "A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband developed microsatellite instability (MSI)– CRC age 23 years
      arising from a serrated polyp, in the setting of multiple (>50) large
      serrated polyps throughout the colon
    explanation: >-
      More than 50 large serrated polyps in a germline RNF43 carrier.
  - reference: PMID:39546056
    reference_title: "Germline pathogenic variants in RNF43 in patients with and without serrated polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Colonoscopies in the probands of these families did not reveal any
      serrated polyps and/or CRC despite some of them being relatively old.
    explanation: >-
      Shows the phenotype is absent in some carriers, so no frequency is
      recorded.
  sequelae:
  - target: Colorectal Carcinoma
    description: >-
      Serrated polyps progress to carcinoma along the serrated neoplasia
      pathway.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- category: Neoplastic
  name: Colorectal Carcinoma
  description: >-
    Colorectal cancer, which can be early-onset in the reported kindreds (one
    proband at age 23). Population data show only a moderate overall risk
    increase, concentrated in N-terminal variants, and some carriers' cancers
    develop without contribution from the germline variant.
  phenotype_term:
    preferred_term: Colorectal cancer
    term:
      id: HP:0003003
      label: Colon cancer
  evidence:
  - reference: PMID:27081527
    reference_title: "A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband developed microsatellite instability (MSI)– CRC age 23 years
      arising from a serrated polyp, in the setting of multiple (>50) large
      serrated polyps throughout the colon
    explanation: >-
      Early-onset colorectal cancer arising from a serrated polyp in a germline
      RNF43 carrier.
  - reference: PMID:41443981
    reference_title: "Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNF43 is a CRC predisposition gene, but risks are moderate, the reported
      polyposis phenotype is often absent and molecular phenocopies can occur.
    explanation: >-
      Supports colorectal cancer as a phenotype while bounding the risk as
      moderate.
genetic:
- name: RNF43
  gene_term:
    preferred_term: RNF43
    term:
      id: hgnc:18505
      label: RNF43
  relationship_type: CAUSATIVE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_9abf2a1d-21a7-4ef7-99c7-b0b37d5acf38-2022-12-30T180000.000Z
    evidence:
    - reference: CGGV:assertion_9abf2a1d-21a7-4ef7-99c7-b0b37d5acf38-2022-12-30T180000.000Z
      reference_title: "RNF43 / sessile serrated polyposis cancer syndrome (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "RNF43 | HGNC:18505 | sessile serrated polyposis cancer syndrome | MONDO:0014919 | AD | Definitive"
      explanation: ClinGen gene-disease validity record classifying this pair as Definitive (AD).
  notes: >-
    The Definitive classification is for the RNF43-defined MONDO term, not for
    clinical serrated polyposis syndrome as a whole. Position matters: in
    population data N-terminal germline truncations raised colorectal cancer risk
    while C-terminal truncations showed no increased risk, so a C-terminal
    variant should not be read as conferring the risks of the reported kindreds.
  evidence:
  - reference: PMID:41443981
    reference_title: "Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Germline C-terminal mutations conferred no increased CRC risk."
    explanation: >-
      Genotype-phenotype result: risk is confined to N-terminal variants in this
      case-control analysis.
  - reference: PMID:41443981
    reference_title: "Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, while 23 CRC/polyp cases and 47 controls from 100kGP or UKB had
      germline RNF43 mutations, cases often lacked multiple polyps or a notable
      family history.
    explanation: >-
      Germline RNF43 variants occur in unselected controls and in cases without
      polyposis, so carriage alone does not establish the syndrome.
diagnosis:
- name: Clinical diagnosis of serrated polyposis by WHO 2019 criteria
  description: >-
    The clinical syndrome is diagnosed endoscopically by cumulative serrated
    polyp count, size and location under the WHO 2019 criteria (at least 5
    serrated lesions proximal to the rectum, all at least 5 mm and at least 2 of
    10 mm or more; or more than 20 serrated lesions throughout the colon with at
    least 5 proximal to the rectum). These criteria define clinical SPS, not
    this RNF43-defined entry: a carrier may not meet them.
  diagnosis_term:
    preferred_term: colonoscopy
    term:
      id: NCIT:C16450
      label: Colonoscopy
  evidence:
  - reference: PMID:41002021
    reference_title: "Low Yield of Genetic Testing in Serrated Polyposis Syndrome."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (i) ≥5 serrated lesions/polyps proximal to the rectum all being ≥5 mm in
      size, with ≥2 being ≥10 mm in size or (ii) >20 serrated lesions/polyps of
      any size distributed throughout the large bowel, with ≥5 being proximal to
      the rectum
    explanation: >-
      States the WHO 2019 diagnostic criteria in the paper's introduction.
  - reference: PMID:35988960
    reference_title: "Serrated polyposis syndrome; epidemiology and management."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: >-
      Both epigenetic and environmental factors, especially smoking, have been
      related to this syndrome, but the etiology of SPS remains uncertain and
      diagnosis is based on endoscopic criteria.
    explanation: >-
      Review stating that SPS diagnosis rests on endoscopic criteria and that
      non-genetic factors contribute.
- name: Germline multigene panel testing including RNF43
  description: >-
    Germline testing of a multigene colorectal cancer and polyposis panel that
    includes RNF43 identifies this entry. The yield of an RNF43 variant in
    clinically defined SPS is low: 1 of 139 panel-tested patients in a UK
    registry, 1 of 73 tested patients in a second UK series, and none of 26 in a
    Dutch cohort. Panel testing in SPS also detects other syndromes, notably Lynch
    syndrome and MUTYH-associated polyposis.
  diagnosis_term:
    preferred_term: germline genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41002021
    reference_title: "Low Yield of Genetic Testing in Serrated Polyposis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On multigene panel testing, pathogenic germline variants were found in 4
      patients (2.9%), including 3 with Lynch syndrome (2 with PMS2 , one with
      MSH2 ) and one with an RNF43 variant.
    explanation: >-
      One RNF43 variant among 139 panel-tested WHO-criteria SPS patients at St
      Mark's Hospital.
  - reference: PMID:35128723
    reference_title: "Germline variant testing in serrated polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy-three patients underwent genetic testing and 15/73 (20.5%) were
      found to have germline variants, of which 7/73 (9.6%) had a pathogenic
      variant (MUTYH n = 2, SMAD4 n = 1, CHEK2 n = 2, POLD1 n = 1, and RNF43 n
      = 1).
    explanation: >-
      One RNF43 pathogenic variant among 73 tested SPS patients in Oxford.
  - reference: PMID:33098683
    reference_title: "RNF43 mutation analysis in serrated polyposis, sporadic serrated polyps and Lynch syndrome polyps."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No germline RNF43 pathogenic variants were detected in our SPS cohort."
    explanation: >-
      No RNF43 pathogenic variants in 26 SPS patients sequenced for all RNF43
      exons.
treatments:
- name: Colonoscopic Surveillance with Polypectomy
  description: >-
    Regular colonoscopy with removal of serrated and adenomatous polyps. The
    surveillance data come from clinically defined SPS cohorts, not from RNF43
    carriers specifically. In those cohorts advanced neoplasia is common during
    surveillance while colorectal cancer incidence is low, and a randomized
    trial could not show that a 3-year interval is non-inferior to a 2-year
    interval. For RNF43 carriers, the source recommends individually tailored
    colonoscopy taking account of variant position and polyp history.
  treatment_term:
    preferred_term: colonoscopic polypectomy
    term:
      id: NCIT:C51688
      label: Colonoscopic Polypectomy
  target_mechanisms:
  - target: Serrated Colorectal Polyps
    treatment_effect: INHIBITS
    description: >-
      Removes polyps before they progress; does not correct the germline
      defect.
  evidence:
  - reference: PMID:30068004
    reference_title: "High incidence of advanced colorectal neoplasia during endoscopic surveillance in serrated polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with SPS have a substantial risk of developing advanced neoplasia
      under endoscopic surveillance, whereas CRC incidence is low.
    explanation: >-
      Multicentre SPS surveillance cohort (not genotyped for RNF43) supporting
      surveillance with polyp removal.
  - reference: PMID:42012787
    reference_title: "Endoscopic Surveillance in Serrated Polyposis Syndrome, Two or Three-Year Intervals: A Non-inferiority Randomized Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with serrated polyposis syndrome, extending colonoscopy
      surveillance to a three-year compared with a two-year interval yielded
      inconclusive evidence regarding non-inferiority for advanced neoplasia
      incidence.
    explanation: >-
      Randomized trial in WHO-criteria SPS; the surveillance interval is not
      settled.
  - reference: PMID:41443981
    reference_title: "Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data do, however, suggest that once a germline RNF43 variant has been
      identified, a pragmatic screening approach is required, for example
      managing patients individually by regular colonoscopy, tailored to the
      position of the germline variant, polyp formation and progression over
      time.
    explanation: >-
      RNF43-specific management suggestion from the authors of the largest
      carrier study.
- name: Colectomy for Unmanageable Polyp Burden or Cancer
  description: >-
    (Sub)total colectomy is used when polyp burden cannot be controlled
    endoscopically or cancer develops; endoscopic surveillance of the remaining
    rectum or sigmoid continues afterwards. Data are from clinically defined SPS,
    not RNF43 carriers specifically.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: colectomy
    term:
      id: NCIT:C15209
      label: Colectomy
  target_mechanisms:
  - target: Colorectal Carcinoma
    treatment_effect: INHIBITS
    description: Removes the at-risk colon.
  evidence:
  - reference: PMID:31403493
    reference_title: "Low Incidence of Advanced Neoplasia in Serrated Polyposis Syndrome After (Sub)total Colectomy: Results of a 5-Year International Prospective Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(Sub)total colectomy mitigates much of the excess risk of CRC in patients with SPS."
    explanation: >-
      Prospective cohort of 48 SPS patients after colectomy with no colorectal
      cancer during follow-up.
  - reference: PMID:30068004
    reference_title: "High incidence of advanced colorectal neoplasia during endoscopic surveillance in serrated polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After total colectomy, 17.9 % patients developed advanced neoplasia in the retained rectum."
    explanation: >-
      Supports continued rectal surveillance after colectomy.
- name: Genetic Counseling and Cascade Testing
  description: >-
    Genetic counseling for individuals with SPS and their relatives, and
    cascade testing of relatives once an RNF43 variant is found. Because
    penetrance is incomplete, counseling of carriers without polyposis is
    difficult and the value of predictive testing in healthy relatives is not
    settled.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31673925
    reference_title: "Hereditary or Not? Understanding Serrated Polyposis Syndrome."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: >-
      Referral for genetic counseling and testing is recommended for
      individuals with serrated polyposis syndrome and a personal history of
      coexisting adenomatous polyposis or with a concerning family history and
      can be considered for all individuals with serrated polyposis syndrome.
    explanation: Review recommendation on when to refer for genetic counseling.
  - reference: PMID:39546056
    reference_title: "Germline pathogenic variants in RNF43 in patients with and without serrated polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This highlights the complexity of genetic counseling in RNF43 positive
      families, and whether healthy relatives should be offered predictive
      testing.
    explanation: >-
      Danish family series raising the unresolved question of predictive
      testing in relatives.
discussions:
- discussion_id: rnf43_yield_in_clinical_sps
  kind: KNOWLEDGE_GAP
  attaches_to:
  - disease#Sessile Serrated Polyposis Cancer Syndrome
  - genetic#RNF43
  prompt: >-
    How much of clinically defined serrated polyposis syndrome does germline
    RNF43 explain, and is the RNF43-defined entity a subtype of SPS or a
    separate predisposition that sometimes presents as SPS?
  rationale: >-
    MONDO places the RNF43-defined term under the clinical syndrome, but cohort
    yields of RNF43 in WHO-criteria SPS are low (none of 26 in a Dutch cohort, 1
    of 73 and 1 of 139 in two UK series, 5 of 304 in a multinational study cited
    as background), and a review puts all identifiable germline causes below 3%.
    In the other direction, population carriers often lack polyposis. The
    overlap between the two concepts is therefore partial in both directions,
    which is why this entry follows the MONDO split rather than lumping clinical
    SPS into it. Whether the residual clinical SPS has an undiscovered
    Mendelian cause, a polygenic or environmental basis (smoking is
    associated), or both, is open.
  evidence:
  - reference: PMID:33098683
    reference_title: "RNF43 mutation analysis in serrated polyposis, sporadic serrated polyps and Lynch syndrome polyps."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a large multinational cohort found five of 304 (1.6%) tested SPS patients
      with probably pathogenic RNF43 variants.
    explanation: >-
      Background citation of a multinational yield. The primary letters this
      sentence cites have no abstract in the reference cache, so the figure
      could not be checked against them; one of them (Buchanan et al., Gut 2017)
      is titled as reporting a lack of evidence for germline RNF43 variants in
      SPS, which shows how contested the yield is.
  - reference: PMID:31673925
    reference_title: "Hereditary or Not? Understanding Serrated Polyposis Syndrome."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: >-
      However, less than 3% of serrated polyposis syndrome cases are explained
      by identifiable germline mutations, with mutations in RNF43 being the only
      currently validated genetic cause.
    explanation: Review estimate of the germline-explained fraction of SPS.
  - reference: PMID:35988960
    reference_title: "Serrated polyposis syndrome; epidemiology and management."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: >-
      Besides a small proportion of cases caused by germline mutations in RNF43,
      no clear genetic cause has been identified.
    explanation: Review stating that RNF43 explains only a small proportion of SPS.
- discussion_id: rnf43_penetrance_and_surveillance_start
  kind: KNOWLEDGE_GAP
  attaches_to:
  - inheritance#Autosomal dominant with incomplete penetrance
  - treatments#Colonoscopic Surveillance with Polypectomy
  prompt: >-
    What is the age-specific penetrance of germline RNF43 variants by variant
    position, and at what age should surveillance of an asymptomatic carrier
    (including a carrier identified as a child through cascade testing) begin?
  rationale: >-
    The family-based literature suggested a high-risk dominant syndrome, with
    colorectal cancer as early as age 23, but population sequencing shows a
    moderate overall risk concentrated in N-terminal variants, and Danish
    families include older carriers with normal colonoscopy. None of the sources
    cited in this entry gives an age to start colonoscopy in RNF43 carriers or
    addresses predictive testing of minors; the surveillance data come from
    adults with clinical SPS. This matters for pediatric cascade testing,
    because the case for testing a child depends on a surveillance action
    taken in childhood or early adulthood.
  evidence:
  - reference: PMID:41443981
    reference_title: "Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In case-control analyses, germline RNF43 variants were associated with CRC
      risk (OR=2.696, p=0.010), but penetrance was much greater for germline
      mutations in the N-terminal half of the gene.
    explanation: Position-dependent risk without age-specific penetrance.
  - reference: PMID:39546056
    reference_title: "Germline pathogenic variants in RNF43 in patients with and without serrated polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This highlights the complexity of genetic counseling in RNF43 positive
      families, and whether healthy relatives should be offered predictive
      testing.
    explanation: States that predictive testing of healthy relatives is unresolved.
references:
- reference: PMID:24512911
  title: Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.
  findings: []
- reference: PMID:27081527
  title: A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred.
  findings: []
- reference: PMID:27329244
  title: RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation.
  findings: []
- reference: PMID:22895187
  title: Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors.
  findings: []
- reference: PMID:41443981
  title: Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis.
  findings: []
- reference: PMID:39546056
  title: Germline pathogenic variants in RNF43 in patients with and without serrated polyposis syndrome.
  findings: []
- reference: PMID:41002021
  title: Low Yield of Genetic Testing in Serrated Polyposis Syndrome.
  findings: []
- reference: PMID:35128723
  title: Germline variant testing in serrated polyposis syndrome.
  findings: []
- reference: PMID:33098683
  title: RNF43 mutation analysis in serrated polyposis, sporadic serrated polyps and Lynch syndrome polyps.
  findings: []
- reference: PMID:31673925
  title: Hereditary or Not? Understanding Serrated Polyposis Syndrome.
  findings: []
- reference: PMID:35988960
  title: Serrated polyposis syndrome; epidemiology and management.
  findings: []
- reference: PMID:30068004
  title: High incidence of advanced colorectal neoplasia during endoscopic surveillance in serrated polyposis syndrome.
  findings: []
- reference: PMID:31403493
  title: "Low Incidence of Advanced Neoplasia in Serrated Polyposis Syndrome After (Sub)total Colectomy: Results of a 5-Year International Prospective Cohort Study."
  findings: []
- reference: PMID:42012787
  title: "Endoscopic Surveillance in Serrated Polyposis Syndrome, Two or Three-Year Intervals: A Non-inferiority Randomized Trial."
  findings: []

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References & Deep Research

References

14

PMID:24512911

Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.