Show Notes
️ Episode 142: Specifications of the ACMG/AMP Guidelines for PALB2 Variant Interpretation
In this episode of PaperCast Base by Base, we explore how the Hereditary Breast, Ovarian, and Pancreatic Cancer Variant Curation Expert Panel (HBOP VCEP) developed gene-specific ACMG/AMP guidelines for the interpretation of PALB2 germline sequence variants, a key gene in hereditary cancer syndromes.
Study Highlights:
The HBOP VCEP assembled an international team of experts to refine the 2015 ACMG/AMP framework specifically for PALB2, a tumor suppressor gene involved in homologous recombination repair. They systematically reviewed 28 evidence codes, advising against the use of 13, limiting six, and tailoring nine to account for PALB2-specific biology. These specifications were validated through the curation of 39 pilot variants, achieving 84% concordance with ClinVar entries and leading to the reclassification of several variants of uncertain significance. The work emphasized the rarity of pathogenic missense variation in PALB2, focusing instead on loss-of-function mechanisms and evidence-based population frequency cutoffs.
Conclusion:
These conservative, PALB2-specific guidelines enhance the accuracy and consistency of variant classification, improving genetic counseling and risk management for individuals with PALB2-related cancer predisposition.
Reference:
Richardson, M.E., Bishop, M.F.H., Holdren, M.A., de la Hoya, M., Spurdle, A.B., Tavtigian, S.V., Brannan, T., Young, C.C., Zec, L., Hiraki, S., Turnbull, C., Tischkowitz, M., Bernstein, K.A., Masson, J.-Y., McNulty, S.M., Pesaran, T., Monteiro, A.N., Walker, L.C., Foulkes, W.D., & Couch, F.J. (2025). Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants. *The American Journal of Human Genetics*, 112(10), 1–15. https://doi.org/10.1016/j.ajhg.2025.08.020
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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