BRCA sequencing of tumors: understanding its implications in the oncology community

In the current era of personalized medicine, much more information can be gleaned through genetic testing and tumor sequencing. Unfortunately, this comes at a price of obtaining results that may beget more uncertainties. Sequencing for mutations on tumor samples is increasingly performed, more commonly to guide treatment for oncology patients, and occasionally as a proxy for germline testing when the ideal index patient to initiate genetic testing in a family at risk for hereditary cancer syndrome is no longer alive. Next-generation sequencing (NGS) involving tens to hundreds of genes as a testing platform is being used more routinely in the clinic now. However, one should keep in mind that the larger number of genes included in an NGS panel will yield a correspondingly higher probability of finding an incidental germline pathogenic mutation, which will have both clinical and ethical implications for patients and their families. The probability of identifying a tumor pathogenic BRCA1/2 variant is about 3-4%, with the majority (~80%) being germline in nature; thus, patients should be counselled accordingly prior to having their tumor samples sequenced. On the flip side, caution should be exercised when tumor sequencing is intended to be a surrogate for germline testing. This is because false negative rate is high at ~30%, making it an inadequate tool to sufficiently dismiss the presence of a germline BRCA1/2 mutation, especially in a setting where there is already a high clinical suspicion for a hereditary condition.