Beyond CDH1: expanded multigene testing reveals additional predisposition genes in hereditary gastric cancer in Brazil

Background Familial predisposition accounts for around 10% of gastric cancers (GC), and 1–3% are linked to germline pathogenic variants (GPVs) in known high-penetrance GC predisposition genes. However, comprehensive analyses of hereditary GC remain limited, as current strategies remain largely centered on CDH1 -associated hereditary diffuse gastric cancer. We aimed to assess the contribution of GPVs in CDH1 and other cancer predisposing genes (CPGs) to familial and early-onset GC. Methods We applied five expanded clinical criteria to identify patients at risk for hereditary GC. Genetic testing was performed in 115 patients with intestinal, diffuse, or mixed gastric cancer using multigene panels containing 26–113 CPGs. Results GPVs were identified in 15.7% of patients, including CDH1 (4.3%), MUTYH monoallelic (4.3%), TP53 (3.5%—all were the p.Arg337His founder variant), ATM (1.7%), and CHEK2 and MLH1 (0.9% each). Additionally, 6% of patients had prioritized variants of uncertain significance. We compared the prevalence of MUTYH p.Gly396Asp and p.Tyr179Cys in the full GC cohort (290 patients) with a Brazilian control population (OR: 2.2; 95% CI 0.96–4.93; p = 0.06). Patients with tumors located in the distal esophagus or cardia showed a higher frequency of GPVs (38.9%) than those with tumors in other sites (12.4%) ( p = 0.01). GPVs did not significantly impact other clinical features. Conclusions In this exploratory Brazilian cohort, multigene testing revealed a heterogeneous spectrum of GPVs beyond CDH1 , including the recurrent TP53 p.Arg337His founder variant, highlighting the value of comprehensive oncogenetic assessment and population-specific context when considering germline testing.