For almost two decades, breast cancer clinical genetics has operated in an environment where a heritable cause of breast cancer susceptibility is identified in the vast minority of women seeking advice about their personal and/or family history of breast and/or ovarian cancer. A new wave of genetic information is upon us that promises to provide an explanation for the greater proportion of current missing heritability of breast cancer. Whilst researchers refine bioinformatic and analytic methodology necessary to interpret the new genetic data, attention needs to be paid to defining appropriate and coordinated pathways for the translation of this information so that it can be applied in clinical genetic services for the benefit of the majority of women who currently have no explanation for their breast cancer susceptibility. The search for additional breast cancer susceptibility genes remains a very active area of research. Exhausting the power of linkage studies that identified BRCA1 and BRCA2, the research community moved to candidate gene studies that led to the identification of ATM, BRIP1, CHEK2, and PALB2 as so-called "moderate-risk" breast cancer susceptibility genes. Mutations in these genes are rare and although early reports suggested that, on average, they are associated with moderate risks of breast cancer; population-based studies have demonstrated that at least some mutations in these genes are associated with breast cancer risks that are comparable to the average risk associated with BRCA2 mutations. The search for additional breast cancer susceptibility genes has now moved onto research platforms applying massively parallel sequencing capable of sequencing whole human exomes and genomes in single instrument runs. These programs are identifying a large number of additional putative breast cancer susceptibility genes, many of which are currently undergoing validation. It is highly anticipated that the remaining missing heritability of breast cancer will be due to mutations in many different genes, each explaining a small proportion of the currently unexplained heritable breast cancer susceptibility. The characterization of PALB2 as a breast cancer susceptibility gene and subsequent research that has refined our understanding of the prevalence and penetrance of heritable mutations in PALB2 offers a precious opportunity to use the data as a model and develop modes of translation that would be appropriate for the anticipated volume of imminent new information.
Keywords: PALB2; breast cancer risk; clinical genetics; translation.