UK consensus recommendations for onward testing for Lynch syndrome in patients with deficient mismatch repair (dMMR) non-colorectal/non-endometrial cancers

Background Tumour testing for microsatellite instability (MSI) or mismatch repair deficiency (dMMR) is used to screen for Lynch syndrome (LS) and as a biomarker for response to immune checkpoint inhibitors, driving tumour-agnostic testing. Germline testing is generally recommended when the likelihood of LS is ≥10%. We aimed to develop a tumour-agnostic framework to identify and triage patients with dMMR/MSI cancers requiring further investigations for possible Lynch syndrome. Methods A scoping review of the literature examined the proportion of MSI and/or MLH1 loss attributable to MLH1 promoter hypermethylation, LS and biallelic somatic MMR gene inactivation across cancer types. These data informed recommendations for MLH1 promoter methylation testing and for germline and somatic MMR gene analysis while considering additional factors relevant to NHS-funded genomic testing. Results We propose unified indications for MLH1 promoter methylation, germline and somatic MMR gene testing following MSI/dMMR detection across tumour types. High-yield cancers (urinary tract, small bowel, pancreatic, adrenocortical, sebaceous carcinoma, glioma) warrant upfront germline testing. MLH1 promoter methylation testing is omitted in these tumour types because MLH1-driven dMMR is rare or insufficiently characterised. A significant proportion of MSI gastric cancers show MLH1 hypermethylation, supporting methylation triage for germline testing in these tumours, alongside MSI/MLH1-deficient colorectal and endometrial cancers. Somatic sequencing should be used selectively to identify double-somatic MMR inactivation when clarifying hereditary risk will influence family management. Conclusion This consensus provides a national framework for post-MSI/MMR evaluation, balancing diagnostic yield, resource use and clinical utility.