Contribution of large genomic rearrangements in <i>PALB2</i> to familial breast cancer: implications for genetic testing.

Abstract

<i>PALB2</i> is the most important contributor to familial breast cancer after <i>BRCA1</i> and <i>BRCA2</i>. Large genomic rearrangements (LGRs) in <i>BRCA1</i> and <i>BRCA2</i> are routinely assessed in clinical testing and are a significant contributor to the yield of actionable findings. In contrast, the contribution of LGRs in <i>PALB2</i> has not been systematically studied. We performed targeted sequencing and real-time qPCR validation to identify LGRs in <i>PALB2</i> in 5770 unrelated patients with familial breast cancer and 5741 cancer-free control women from the same Australian population. Seven large deletions ranging in size from 0.96 kbp to 18.07 kbp involving <i>PALB2</i> were identified in seven cases, while no LGRs were identified in any of the controls. Six LGRs were considered pathogenic as they included one or more exons of <i>PALB2</i> and disrupted the WD40 domain at the C terminal end of the PALB2 protein while one LGR only involved a partial region of intron 10 and was considered a variant of unknown significance. Altogether, pathogenic LGRs identified in this study accounted for 10.3% (6 of 58) of the pathogenic <i>PALB2</i> variants detected among the 5770 families with familial breast cancer. Our data show that a clinically important proportion of <i>PALB2</i> pathogenic mutations in Australian patients with familial breast cancer are LGRs. Such observations have provided strong support for inclusion of <i>PALB2</i> LGRs in routine clinical genetic testing.