Tumor-only sequencing for oncology management: Germline-focused analysis and implications

As patients are now routinely having large somatic genomic testing panels undertaken as part of routine management, there is the rising likelihood of uncovering the presence of a germline pathogenic variant. This may be found on testing undertaken on plasma (ctDNA) or tissue. This has led to the need for clear guidelines for oncologists about how to manage such results, including which variants require validation, how this should be undertaken, and what potential problems may arise. This requires an understanding of the limits of testing, and the pitfalls that may be encountered. In this review, we assess the frequency of detecting germline variants through tumor-only sequencing, the necessary considerations for such information to be analyzed and the role of the molecular tumor board in considering results. We assess the additional considerations for interpretation of the underlying tumor, use of ctDNA or tissue for testing, clonal hematopoiesis, and hypermutation.