Best Practice for Clinical Somatic Variant Interpretation and Reporting

Key points

Introduction

During the past decade, there has been an increased push toward the development of precision cancer medicine, in hopes of tailoring treatments that effectively induce a therapeutic response based on the genomic profile of an individual’s tumor. 123 Concurrently, there have been tremendous improvements in reducing cost and increasing the speed and capacity of next generation sequencing (NGS) technologies, as well as in the development of sophisticated bioinformatics tools. As NGS-based clinical tests have become more accessible and widely used, the amount of data generated has increased substantially. ^4 , 5 Although tumor sequencing previously focused on variants in known hotspot regions, more recently these small targeted hotspot panels are being replaced by much broader strategies, ranging from panels with hundreds of cancer-associated genes to much more open-ended methods such as whole genome sequencing, creating an explosion of cancer genomic data. ^6 , 7 With such an increase in the breadth of tumor sequencing, it is now critical to have an efficient, reliable, and reproducible method of interpreting how a patient’s variants may inform cancer care.

The 2017 Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists (AMP/ASCO/CAP) standards and guidelines for the interpretation and reporting of sequence variants in cancer ⁸ are the first set of professional recommendations for laboratories to share a common system of somatic variant classification, similar to the American College of Medical Genetics and Genomics (ACMG)/AMP guidelines for constitutional variants. ⁹ A standardized and more universal approach is necessary to avoid inconsistencies in variant interpretation and reporting, as different clinical laboratories and institutions had established their own sets of standards with unique terminologies before the release of the 2017 guidelines. 101112 Additionally, considering that specific genetic patterns or abnormalities are now included in official tumor classification and treatment guidelines, 131415 it is increasingly important for laboratory professionals to share a common language with oncologists to accurately define the genetic context of a patient’s tumor.

The 2017 AMP/ASCO/CAP guidelines proposed the following 4-tiered system of variant classification to serve as this common language: Tier I, variants of strong clinical significance; Tier II, variants of potential clinical significance; Tier III, variants of unknown clinical significance; and Tier IV, benign or likely benign variants. To assign the appropriate tier, the guidelines suggest using clinical and experimental evidence that would directly inform patient care or drive clinical decision-making. There are 4 proposed levels of evidence, A, B, C, and D, which have decreasing degrees of significance regarding 3 considerations on clinical impact: (1) therapeutic response or resistance, (2) diagnosis, and (3) prognosis. A visual representation and explanation of variant tiers and levels of evidence can be seen in Fig. 1 .