Comprehensive analysis of germline and somatic SDHA alterations reveals rare incidental germline variants and prognostic implications of somatic loss in breast cancer

Multigene panel testing (MGPT) has increased the detection of SDHA pathogenic/likely pathogenic (P/LP) variants in cancer patients, but their clinical interpretation remains challenging due to low penetrance and lack of gene-specific variant interpretation guidelines. This study aimed to evaluate the prevalence and clinical relevance of germline and somatic SDHA P/LP variants in cancer patients. A total of 1,699 consecutively referred cancer patients underwent MGPT between 2021 and 2023. Population controls were obtained from the gnomAD database. When available, tumour samples were analysed for RNA-level characterisation and SDHA loss of heterozygosity (LOH). In addition, SDHA copy number variations (CNVs) were assessed in 10,463 pan-cancer and 8,037 breast tumour samples in silico. Germline SDHA variants were rare: 19 heterozygous variants (8 P/LP and 11 variants of unknown significance (VUS)) were identified. No association between SDHA variants and tumour types was observed, and LOH was absent in non-SDHA-associated tumours. AI-based functional predictions suggested potential pathogenicity for a subset of VUS, but their role remained uncertain. Somatic SDHA deletions were detected in 2.5% of pan-cancer and 5.4% of breast tumour samples. In breast cancer, SDHA CNV loss was associated with significantly worse overall and relapse-free survival (HR = 1.55 and 1.48, respectively; P < 0.05). However, CNVs extended across a 375 kb region around the SDHA locus, suggesting that this association may be related to 5p chromosomal deletions rather than the SDHA loss alone. In conclusion, germline SDHA variants are rare and likely incidental in most cancers, but somatic 5p chromosomal deletions, including SDHA in breast cancer, may have a prognostic value.