This study reports recurrent somatic mutations in the EZH2 gene, specifically a mutation at position Y641 in the SET domain, which is associated with follicular lymphoma (FL) and the germinal center B-cell (GCB) subtype of diffuse large B-cell lymphoma (DLBCL). The mutation, which replaces a single tyrosine with a histidine, occurs in 21.7% of GCB DLBCLs and 7.2% of FLs, but is absent in activated B-cell (ABC) DLBCLs. The mutation is predicted to reduce the enzymatic activity of EZH2 in vitro, and the authors confirm that it is somatic and heterozygous in nature. The mutation is not found in non-malignant germinal center B-cells or other types of lymphoma, suggesting its specific role in these lymphomas. The study also highlights the importance of EZH2 in B-cell development and its potential role in lymphomagenesis, distinct from its known functions in breast and prostate cancers. The findings provide new insights into the genetic basis of GCB lymphomas and suggest that EZH2 Y641 mutations may contribute to the differential DNA methylation observed in these cancers.This study reports recurrent somatic mutations in the EZH2 gene, specifically a mutation at position Y641 in the SET domain, which is associated with follicular lymphoma (FL) and the germinal center B-cell (GCB) subtype of diffuse large B-cell lymphoma (DLBCL). The mutation, which replaces a single tyrosine with a histidine, occurs in 21.7% of GCB DLBCLs and 7.2% of FLs, but is absent in activated B-cell (ABC) DLBCLs. The mutation is predicted to reduce the enzymatic activity of EZH2 in vitro, and the authors confirm that it is somatic and heterozygous in nature. The mutation is not found in non-malignant germinal center B-cells or other types of lymphoma, suggesting its specific role in these lymphomas. The study also highlights the importance of EZH2 in B-cell development and its potential role in lymphomagenesis, distinct from its known functions in breast and prostate cancers. The findings provide new insights into the genetic basis of GCB lymphomas and suggest that EZH2 Y641 mutations may contribute to the differential DNA methylation observed in these cancers.