Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk
Year: 2026
Type: article
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. The impact of variants of uncertain significance (VUS) on protein function and cancer risk remain unclear. Here, the authors focus on the functional impact of VUS of the PALB2 gene and identify defects in DNA damage repair by homologous recombination associated with increased risk of breast cancer.
Source: Nature Communications
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, Zdenek Kleibl, Marta Cerna, Barbora Konecna, Katerina Matejkova, Petr Nehasil, Tatana Ptackova, Jana Soukupova, Lenka Foretova, Eva Machackova, Vera Krutilkova, Spiros Tavandzis, Monika Koudova, Leona Cerna, Stepan Chvojka, Ondrej Havranek, Jan Novotny, Kamila Vesela, Michal Vocka, Renata Michalovska, Lucie Hruskova, Helena Paszekova, Denisa Schwetzova, Zdenka Vlckova, Ivan Subrt, Monika Cerna, Marketa Hejnalova, Nikol Jedlickova, Tomas Zavoral, Marcela Kosarova, Gabriela Vacinova, Maria Janikova, Romana Kratochvilova, Vaclava Curtisova, Ondrej Scheinost, Petra Duskova, Miroslav Fiser, Daniel Panchartek, Martin Schwartz, Lucie Faldynova, Michaela Necesankova, Marcy E. Richardson, Susan L. Kloet, Fergus J. Couch, Maaike P. G. Vreeswijk, Haico van Attikum
Institutions: Leiden University Medical Center, Charles University, General University Hospital in Prague, Mayo Clinic, Memorial Sloan Kettering Cancer Center, Cornell University, Weill Cornell Medical Center, Bio-Prodict (Netherlands), Ambry Genetics (United States), University Hospital Plzen, Masaryk Memorial Cancer Institute, Gennet, University Hospital Olomouc, Palacký University Olomouc, Nemocnice České Budějovice, University Hospital Ostrava
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1005326806, G1039539235, G1390403097, G1729689623, G2004299919, G2051006376, G2090698944, G240128644, G2688475449, G2868665970, G289723095, Verbetering van de interpretatie van de DNA-uitslag bij erfelijk borst- en eierstokkanker door het gebruik van functionele gen-testen, G3562932637, G3602505857, Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES), G3978591521, G434337789, G444765703, G705811388, G7166160813, G7796364618, G782458776, G8538768952, G9000003249, G9000230166, Cancer Center Support Grant
OpenAlex ID: W7124771272