Show Notes
In this episode of Base by Base, we explore a recent study published in The American Journal of Human Genetics that investigates the integration of structural biology into the ACMG/AMP framework for classifying BRCA1 missense variants.
The research assesses how incorporating structure-based evidence—such as relative solvent accessibility (RSA), folding stability (ΔΔG), and AlphaMissense pathogenicity scores—can refine the application of computational evidence codes PP3 and BP4. By utilizing tools like AlphaFold2 and FoldX5.0, the study demonstrates that combining AlphaMissense with ΔΔG predictions enhances the granularity of evidence strength, particularly for variants in the RING and BRCT domains of BRCA1.
Key findings include:
AlphaMissense outperforms traditional tools like BayesDel in predicting variant pathogenicity.
ΔΔG predictions add depth to the interpretation, especially when assessing protein stability.
RSA plays a crucial role, with benign evidence (BP4) being more applicable to variants in buried or partially buried residues.
This episode delves into how these structure-informed scores can improve the classification of BRCA1 missense variants, aiding in more accurate genetic diagnostics.
Reference:Ramadane-Morchadi, L., Rotenberg, N., Esteban-Sánchez, A., et al. (2025). ACMG/AMP interpretation of BRCA1 missense variants: Structure-informed scores add evidence strength granularity to the PP3/BP4 computational evidence. The American Journal of Human Genetics, 112(5), 1–10. https://doi.org/10.1016/j.ajhg.2024.12.011
License:This content is distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). For more information, visit creativecommons.org.
