Beyond the Stain: BAP1 ‐Inactivated Melanocytic Tumors With Retained BAP1 Nuclear Expression due to Missense Mutations in the Catalytic Domain

BAP1-inactivated melanocytic tumors (BIMTs) demonstrate loss of BAP1 nuclear expression by immunohistochemistry (IHC), which serves as a key diagnostic marker. Here, we present four cases of BIMTs with retained BAP1 nuclear expression. All cases demonstrated dual cytomorphology, low mitotic activity, and either absence of PRAME expression or only weak focal expression. Three cases demonstrated BAP1 p.H169Y missense mutations alongside BRAF V600E mutations. In one case, a BAP1 p.G185R missense mutation and a BRAF V600_S602delinsDT mutation were identified. Both BAP1 missense variants were located in the functional ubiquitin carboxyl hydrolase (UCH) domain at the N-terminus. Although most BAP1 mutations are missense, the majority lead to loss of nuclear expression by IHC due to misfolding or impaired nuclear localization. Therefore, IHC directed against the C-terminus of BAP1 protein remains a sensitive diagnostic tool. In contrast, the p.H169Y and p.G185R variants appear to uniquely preserve both protein folding and nuclear localization, allowing retained nuclear expression despite functional inactivation. Therefore, in tumors with morphologic features suggestive of BIMT, retained BAP1 nuclear expression should not preclude diagnosis or additional molecular testing to confirm BAP1 inactivation.