Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk
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.
Authors
- Mária Janíková
- Markéta Janatová (ORCID: https://orcid.org/0000-0003-2816-6769)
- Susan L. Kloet (ORCID: https://orcid.org/0000-0001-9189-0640)
- Kateřina Matějková
- Daniel Panchártek
- Michael Conry (ORCID: https://orcid.org/0000-0003-1904-8947)
- Štěpán Chvojka
- Ondřej Havránek
- Michal Vočka
- Petra Kleiblová (ORCID: https://orcid.org/0000-0002-4806-9854)
- Marcela Kosařová
- Huaizhi Huang (ORCID: https://orcid.org/0009-0001-6186-7228)
- Lucie Hrušková (ORCID: https://orcid.org/0000-0002-4857-2388)
- Magdalena B. Rother
- Matthew J. Varga (ORCID: https://orcid.org/0000-0001-9818-1767)
- Roberta Menafra (ORCID: https://orcid.org/0000-0002-5266-0639)
- Sabine Knaup
- Stephan Heijl (ORCID: https://orcid.org/0000-0001-8920-4293)
- Lucie Faldynová (ORCID: https://orcid.org/0009-0007-1797-5874)
- Michaela Nečesánková
- Merel E. Braspenning
- Eva Macháčková (ORCID: https://orcid.org/0000-0002-0246-1471)
- Rick A.C.M. Boonen
- Haico van Attikum (ORCID: https://orcid.org/0000-0001-8590-0240)
- Zdeněk Kleibl
- Kamila Vesela
- Dina Ruano
- Leona Černá
- Taťána Ptáčková
- Miroslav Fišer
- Petr Nehasil
- Chunling Hu
- Tomas Zavoral
- Martin Schwartz
- Gabriela Vacinova
- Marketa Hejnalova
- Petra Duskova
- Vijai Joseph
- Marcy E. Richardson
- Helena Paszekova
- Nikol Jedlickova
- Denisa Schwetzova
- Ivan Subrt
- Spiros Tavandzis
- Monika Cerna
- Barbora Konecna
- Zdenka Vlckova
- Renata Michalovska
- Lenka Foretova
- Monika Koudova
- Ondrej Scheinost
- Marta Cerna
- Fergus J. Couch
- Jelle J. Goeman
- Bas Vroling
- Jan Novotny
- Vera Krutilkova
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Pardubice (CZ)
- Cornell University (US)
- Charles University (CZ)
- Leiden University Medical Center (NL)
- University Hospital Ostrava (CZ)
- University Hospital Olomouc (CZ)
- Masaryk Memorial Cancer Institute (CZ)
- Mayo Clinic in Arizona (US)
- Nemocnice České Budějovice (CZ)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- Ambry Genetics (United States) (US)
- General University Hospital in Prague (CZ)
- Bio-Prodict (Netherlands) (NL)
- Palacký University Olomouc (CZ)
- University of West Bohemia in Pilsen (CZ)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-19
- DOI
- https://doi.org/10.1038/s41467-025-67252-z
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Breast Cancer Research Foundation
- Memorial Sloan-Kettering Cancer Center
- Univerzita Karlova v Praze
- European Commission
- Ministerstvo Zdravotnictví Ceské Republiky
- National Institutes of Health