Structural biology in variant interpretation: Perspectives and practices from two studies.

Abstract

Structural biology offers a powerful lens through which to assess genetic variants by providing insights into their impact on clinically relevant protein structure and function. Due to the availability of new, user-friendly, web-based tools, structural analyses by wider audiences have become more mainstream. These new tools, including AlphaMissense and AlphaFold, have recently been in the limelight due to their initial success and projected future promise; however, the intricacies and limitations of using these tools still need to be disseminated to the more general audience that is likely to use them in variant analysis. Here, we expound on frameworks applying structural biology to variant interpretation by examining two accompanying articles. To this end, we explore the nuances of choosing the correct protein model, compare and contrast various structural approaches, and highlight both the advantages and limitations of employing structural biology in variant interpretation. Using two articles published in this issue of The American Journal of Human Genetics as a baseline, we focus on case studies in TP53 and BRCA1 to illuminate gene-specific differences in the applications of structural information, which illustrate the complexities inherent in this field. Additionally, we discuss the implications of recent advancements, such as AlphaFold, and provide practical guidance for researchers navigating variant interpretation using structural biology.