Abstract 1014: Detection of reportable germline <i>BAP1</i> mutations in patients with uveal melanoma
Authors: Amy C. Schefler, Julia Litvinov, Jason Maarsing, Kasia Wozny, Olga Zolochevska
Journal: Cancer Research (2025)

Purpose: The reported rate of pathogenic germline mutations in the BAP1 gene range from 2% in unselected population to up to 50% in patients with familial uveal melanoma (UM) and are associated with an increased risk of developing BAP1-Tumor Predisposition Syndrome (TPDS)-related cancers. The primary objective of this study was to determine more accurately the rate of germline BAP1 mutations in a clinically representative sample population of UM patients with a known somatic mutation in BAP1, using clinically available 7-gene UM next-generation sequencing (NGS) panel DecisionDx-UMSeq. Methods: Blood and buccal swab samples were prospectively collected from 45 adult participants (median age at diagnosis 63 y.o., range 35-92) at a single center under an IRB-approved protocol. All participants had a prior diagnosis of primary UM and had at least one reportable BAP1 mutation previously identified in their tumors. Both samples (blood and buccal swab) were analyzed using the DecisionDx-UMSeq test. Results of all 3 assays (tumor, blood, and buccal swab) were analyzed for the presence of BAP1 mutations. Results: All reportable germline mutations detected in blood and buccal swab samples were previously identified in the primary tumor samples by DecisionDx-UMSeq, with 100% concordance in mutation calls between blood and swab samples and allele frequencies (AFs) within a 5% range. Out of 45 samples analyzed, 11 (24.4%) had reportable germline mutations classified as either Variants of Uncertain Significance (VUS) or pathogenic according to the ClinVar database. The remaining 34 samples had no reportable germline mutations. When comparing the AFs of BAP1 mutations in blood and buccal swab to those in tumor samples, 4/11 (36.4%) had matching AFs, while 7/11 (63.6%) exhibited higher AFs in the tumor samples than in blood or buccal swabs. Among the detected mutations, four were classified as pathogenic and seven as VUS. Tumors in this cohort tended to be large, consistent with a high-risk molecular profile, with an average diameter of 14.5±3.53 mm and average tumor thickness of 6.14±3.48 mm. Conclusions: The DecisionDx-UMSeq panel accurately identified reportable germline BAP1 mutations in both buccal swab and blood samples from patients with previously reported somatic BAP1 mutations. A quarter of patients in this cohort had a reportable germline mutation, including patients without a family history suggestive of typical BAP1-TPDS cancers, thus indicating that the rate of BAP1 germline mutations may be higher in this cohort than reported elsewhere. This study supports the routine implementation of the DecisionDx-UMSeq panel for BAP1 germline testing in all patients with a somatic BAP1 mutation, enabling improved critical clinical decision-making and genetic counseling for patients and family members at risk of BAP1-related TPDS. Citation Format: Amy C. Schefler, Julia Litvinov, Jason Maarsing, Kasia Wozny, Olga Zolochevska. Detection of reportable germline BAP1 mutations in patients with uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1014.