Refinement of the UKCGG/CanVIG framework for triage of putative germline variants identified via tumour and ctDNA sequencing: maximising clinical utility and harmonising gene and variant-restricted reporting across UK clinical practice

Variants of possible constitutional origin are frequently identified during analysis of tumour-derived DNA. Building on the European Society for Medical Oncology Precision Medicine Working Group’s recommendations, we previously proposed an intermediate-conservative triage approach adapted for the UK National Health Service (NHS). Given subsequent developments in national policy and variant-specific guidance, we sought to produce a unified, clinically coherent framework that incorporates updated and newly developed recommendations for interpretation, reporting and management. UK guidance on germline and somatic variant interpretation, reporting and follow-up is developed through structured, multidisciplinary consensus processes involving relevant professional groups, aligned with NHS England commissioning and Genomic Medicine Service (GMS) pathways. These processes integrate expert review, published evidence, national policy and iterative consultation across genomic laboratory hubs and clinical genetics services. Recent work has included national guidance on tumour-detected CNVs in cancer susceptibility genes, refinement of somatic and germline variant-specific reporting frameworks, and contributions to guidance on demand management, incidental germline findings and expansion of standard-of-care tumour testing. We synthesised these outputs to generate a harmonised decision model for follow-up of putative germline variants identified through tumour-derived DNA. We present an updated four-tier gene categorisation stratified by clinical and public health utility, incorporating germline conversion rates and explicit entry criteria for germline follow-up. The framework integrates variant-specific reporting guidance and provides unified triage principles for sequence and CNVs. This integrated framework supports consistent, evidence-based triage of tumour-ascertained variants across UK services, aligns with NHS GMS pathways and promotes sustainable, clinically meaningful germline follow-up.