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<p>Loss-of-function variants in <i>PALB2</i> 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 <i>PALB2</i> 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 <i>PALB2</i> 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 <i>PALB2</i> missense VUS and clinical management of carriers.</p>

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Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月19日

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  • 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

摘要

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.