Inherited polyposis and early onset colorectal cancer - germline testing

Gene: RNF43

Red List (low evidence)

R211 - Discussed at UKCGG/Cancer & Scientific Leads meeting 29/1/26
• Strong consensus that SPS-related indication should be removed due to very low diagnostic yield.
• RNF43: Agreement to remove RNF43 from routine panels.
o Recognition that existing RNF43 positive families will require separate management guidance, distinct from SPS phenotype.
o Onward management advice should be guided by phenotype and damily history rather than genotype

Detail below - included in proposal for amendment to R211 submitted to NGTD team March but recording here for visibility too.
A recent retrospective analysis by the team in St Mark's Bowel Hospital (PMID: 41002021) demonstrated a very low yield of germline testing in patients with Serrated Polyposis Syndrome, at a rate of 2.9% (4/573) - well below the 10% diagnostic yield at which germline diagnostic testing is typically recommended. Only a single patient was found to a carry a variant in RNF43.

Personal communication with the National Disease Registration Service shows similarly low yield across the country – data censored at July 2024 indicated 0/498 R211 tests had a positive RNF43 result. Manual interrogation of more recently submitted data indicated a single likely pathogenic variant and 7 variants of uncertain significance. Discussions via the Cancer Variant Interpretation UK forum indicate a number of other VUS have been identified that have not yet been submitted to NDRS and that remain unresolved. The penetrance associated with RNF43 variants is unclear, and no management guidelines have yet been developed for carriers of variants in this gene. At present, the yield is too low, and VUS rate disproportionately burdensome, to justify testing of this gene.

Created: 22 Oct 2026, 2:20 p.m. | Last Modified: 22 Oct 2026, 2:20 p.m.

Panel Version: 4.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
serrated polyposis; colorectal cancer

Publications

• 41002021

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 11:58 a.m. | Last Modified: 8 Mar 2022, 11:59 a.m.

Panel Version: 1.30

Comment on list classification: As discussed in the GMS Inherited Cancer Specialist Test Group webex call 31st Jan 2019: The Specialist Test Group agreed that this gene should be rated amber.

Created: 1 Feb 2019, 10:07 a.m.

Green List (high evidence)