| Title: | Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk |
| Journal: | Nature Communications |
| Published: | 19 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41554690/ |
| DOI: | https://doi.org/10.1038/s41467-025-67252-z |
| URL: | https://www.nature.com/articles/s41467-025-67252-z_reference.pdf |
Publication 18618
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Abstract
Loss-of-function variants in PALB2 give rise to defects in DNA damage repair by homologous recombination (HR), increasing the risk of breast cancer in female carriers. However, genetic testing frequently reveals missense variants of uncertain significance (VUS) for which the impact on protein function and cancer risk are unclear. Here we assay 84% of all possible missense variants in 11 out of 13 PALB2 exons using site-saturation functional screens with PARP inhibitor sensitivity as a readout for HR. These exons encode the coiled-coil and WD40 domains, which we identify as the minimal regions required for HR. Furthermore, we reveal the functional impact of 6718 missense variants, classifying 3904 variants as functional (58%), 2422 as intermediate (36%), and 392 as damaging (6%). A burden-type analysis shows that damaging missense variants in PALB2 are associated with a significantly increased risk of breast cancer, similar to that observed for truncating variants. These results will be valuable for the classification of PALB2 missense VUS and clinical management of carriers.</p>
8 Keywords
- Breast Neoplasms
- Exons
- Fanconi Anemia Complementation Group N Protein
- Female
- Genetic Predisposition to Disease
- Humans
- Mutation, Missense
- Poly(ADP-ribose) Polymerase Inhibitors
21 Authors
- Rick A.C.M. Boonen
- Sabine C. Knaup
- Roberta Menafra
- Merel E. Braspenning
- Magdalena B. Rother
- Petra Kleiblova
- Marketa Janatova
- Dina Ruano
- Chunling Hu
- Huaizhi Huang
- Vijai Joseph
- Michael Conry
- Stephan Heijl
- Bas Vroling
- Jelle J. Goeman
- Matthew Varga
- Marcy E. Richardson
- Susan L. Kloet
- Fergus J. Couch
- Maaike P. G. Vreeswijk
- Haico van Attikum
1 Application
| Application ID | Title |
|---|---|
| 50092 | Delineating Germline Genes that Predispose to Cancer |
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