A novel SDHA L511P variant: evidence supporting reclassification to likely pathogenic

Succinate dehydrogenase (SDH, Complex II) is a known tumor suppressor and key enzyme in the citric acid cycle that converts succinate into fumarate. Heterozygous loss-of-function germline variants in SDH subunit genes can result in Hereditary Paraganglioma and Pheochromocytoma Syndrome (HPPS), which includes paragangliomas and gastrointestinal stromal tumors (GIST). Loss of SDH activity leads to succinate accumulation, which stabilizes the transcription factor HIF-1α, subsequently upregulating pro-proliferative genes. In this case, we report a patient who has an SDHA c.1532T > C, p.Leu511Pro germline variant of unknown significance (VUS), but presents with the two hallmarks of HPPS, as well as papillary thyroid carcinoma. This exact variant associated with HPPS has not yet been reported in the literature. We report a unique case of a 30-year-old patient who presented with a gastric mass, ultimately diagnosed as a GIST. The GIST was resected with negative margins and found to be SDH-deficient. One year later, the patient presented with a neck mass, which was diagnosed as a paraganglioma. The paraganglioma was surgically removed with negative margins. Thirteen years after the GIST diagnosis, the patient developed a worrisome thyroid nodule that was excised and found to be papillary thyroid carcinoma. The patient was treated with a 31.2-mCi therapeutic dose of I-131 sodium iodide. Two years later, the patient developed a recurrent GIST, which was subsequently resected with negative margins. Currently, the patient is disease-free and follows in the adult cancer predisposition clinic. Given that this patient developed both GIST and paraganglioma, two hallmark tumors of HPPS caused by heterozygous loss-of-function mutations in SDH subunit genes, we propose that the SDHA c.1532T > C (p.Leu511Pro) variant be reclassified as “likely pathogenic.” To support this, we performed SDHB immunohistochemistry (IHC), as loss of SDHB expression is expected in tumors harboring pathogenic variants in any SDH subunit gene. This IHC demonstrated complete or partial loss of SDHB expression in all tumors, as assessed by two board-certified bone and soft tissue pathologists.