To screen or not to screen: complexity of

Summary: Pathogenic germline variants in the genes encoding the various subunits of the succinate dehydrogenase (SDH) enzyme complex are strongly associated with hereditary phaeochromocytomas and paragangliomas (PPGLs). Germline pathogenic variants (PGVs) in the SDHA gene are also found in individuals with wild-type gastrointestinal stromal tumours (GISTs) and paragangliomas. However, the penetrance of SDHA variants is relatively low. Only a minority of carriers will develop tumours as a result of the genetic condition. As a result, careful clinical interpretation is therefore required to avoid unnecessary over-investigation or undue concern. Current national guidelines recommend that SDHA variants should only be considered actionable (that is, to lead to surveillance in the proband and family screening) if they are identified in individuals with a personal or family history of an SDHA-related tumour. Nevertheless, SDHA variants are increasingly detected as a result of whole genome sequencing or multigene panel testing. This emphasises the importance of clinical context when deciding on surveillance or family testing. We describe three carriers of germline Learning points: Germline