Frequency of and Germline Variants in Families with Diffuse and Mixed Gastric Cancer.

The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the gene, and more rarely in the gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of and germline variants to HDGC. Additionally, we also intended to compare the frequencies of and (and eventually ) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and the and genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for pathogenic germline variants. A deleterious germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of deleterious variants found by us in this setting. No deleterious variants were found in , but six variants of uncertain significance were identified in this gene. We did not find any pathogenic , or variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the gene in inherited gastric cancer predisposition is still unclear.