Characterization of a novel germline PALB2 duplication in a hereditary breast and ovarian cancer family.

PURPOSE: Mutations in PALB2 have been associated with a predisposition to breast and pancreatic cancers. This study aims to characterize a novel PALB2 exon 13 duplication in a hereditary breast and ovarian cancer family. METHODS: The PALB2 exon 13 duplication in this family was evaluated using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT™) and confirmed by multiplex ligation-dependent probe amplification (MLPA). The duplication breakpoints were determined by long-range PCR and DNA sequencing. The effects of this mutation on mRNA splicing were characterized using RT-PCR, cloning, and DNA sequencing. RESULTS: The 5' and 3' breakpoints were mapped to intron 12 and downstream of 3'UTR. The tandem duplication is mediated by Alu elements in these regions. This duplication disrupts normal mRNA splicing and presumably leads to a frameshift and premature protein truncation. This duplication segregates with ovarian and breast cancer in multiple members in this family. CONCLUSIONS: Our results indicate that the PALB2 exon 13 duplication is a pathogenic variant. The presence of the PALB2 duplication in the proband affected with high-grade serous ovarian cancer suggests that PALB2 might be associated with a predisposition to ovarian cancer.