To screen or not to screen: complexity of SDHA mutation management

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 SDHA variants. The first case is a 72-year-old male with a history of prostate cancer and GIST, where genetic testing revealed germline variants in BRCA2 and SDHA. Tumour-derived DNA from his GIST demonstrated a somatic PDGFRA driver mutation, and SDH staining was preserved, indicating a sporadic PDGFRA-driven GIST rather than a classical SDHA-deficient tumour. While truncating SDHA variants such as this one have been reported in SDH-deficient GIST, the current UK practice considers them low penetrance and typically not actionable in the absence of SDH-deficient pathology. Accordingly, cascade testing of the SDHA variant was not recommended in his family, and no surveillance for SDH-associated tumours was initiated, although we recognise that some international guidelines may take a more precautionary approach. The second case features a 59-year-old female with wild-type GIST and a family history of brain tumours and breast cancer. Testing of tumour-derived DNA identified an SDHA variant, later confirmed of germline origin. Surveillance for other SDH-associated tumours for the proband and cascade testing for her relatives were recommended. The third case involves a man in his sixties with prostate cancer, found to carry an incidental SDHA variant after undergoing broad cancer predisposition panel testing. He had no personal/family history of SDH-associated tumours, and his prostate cancer showed strong SDHA expression, indicating that the variant was non-actionable, and no surveillance for SDH-associated tumours or familial cascade testing was recommended. These cases underscore the importance of interpreting SDHA variants carefully, as the identification of germline SDHA variants does not always indicate the need for aggressive surveillance or intervention. Learning points