Contribution of large genomic rearrangements inPALB2to familial breast cancer: implications for genetic testing

Abstract

BackgroundPALB2is the most important contributor to familial breast cancer afterBRCA1andBRCA2. Large genomic rearrangements (LGRs) inBRCA1andBRCA2are routinely assessed in clinical testing and are a significant contributor to the yield of actionable findings. In contrast, the contribution of LGRs inPALB2has not been systematically studied.MethodsWe performed targeted sequencing and real-time qPCR validation to identify LGRs inPALB2in 5770 unrelated patients with familial breast cancer and 5741 cancer-free control women from the same Australian population.ResultsSeven large deletions ranging in size from 0.96 kbp to 18.07 kbp involvingPALB2were 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 ofPALB2and 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 pathogenicPALB2variants detected among the 5770 families with familial breast cancer.ConclusionsOur data show that a clinically important proportion ofPALB2pathogenic mutations in Australian patients with familial breast cancer are LGRs. Such observations have provided strong support for inclusion ofPALB2LGRs in routine clinical genetic testing.