Peer-Reviewed Publication
Am J Hum Genet2026October 12, 2026Journal Article
Large-scale integration of functional assay data for the resolution of germline BRCA1 and BRCA2 variants of uncertain significance.
Paulo C M Lyra1, Samuel Brito1, Michael Parsons2, Chunling Hu3, Thales C Nepomuceno1, Nam Phuong Nguyen1, Lucas Dalcolmo1, Marcy E Richardson4, Geise de Oliveira5, João da Silva5, Laura Caleca6, Huaizhi Huang3, Sounak Sahu7, Muthiah Bose8, Maria Rossing9, Phoebe Dace10, Gregory M Findlay10, Rehan Villani2, Aditi Hazra11, Alexandra Martins12, Sandrine M Caputo13, Gael A Millot14, Joanne Ngeow Yuen Yie15, Marcelo A Carvalho16, Melissa S Cline17, Paolo Radice6, Romy L S Mesman18, Valentina Zampiga19, Vijai Joseph20, Katherine L Nathanson21, Kyriaki Michailidou22, Edwin S Iversen23, Shyam Sharan7, Amanda B Spurdle2, Maaike P G Vreeswijk17, Fergus J Couch3, Alvaro N A Monteiro24,
1Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
2Population Health Program, QIMR Berghofer, Brisbane, QLD 4006, Australia.
3Mayo Clinic, Rochester, MN, USA.
4Ambry Genetics, Aliso Viejo, CA, USA.
5Centro Universitario FAEMA, Ariquemes, Rondonia, Brazil.
6Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
7Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
8Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
9Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
10The Francis Crick Institute, London, UK.
11Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
12University Rouen Normandie Inserm U1245, 76000 Rouen, France.
13Department of Genetics, Institut Curie, Paris Sciences and Lettres (PSL) University Paris, France.
14Institut Pasteur, Université Paris Cité, Paris 75015, France.
15Lee Kong Chian Schoof of Medicine, Nanyang Technological University Singapore, Singapore, Singapore; Cancer Genetics Service, National Cancer Centre Singapore, Singapore, Singapore.
16Instituto Federal do Rio de Janeiro, Rio de Janeiro 20270-021, Brazil.
17UC Santa Cruz Genomic Institute, Santa Cruz, CA, USA.
18Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
19Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, 47014 Meldola, Italy.
20Memorial Sloan Kettering Cancer Center. New York, New York, NY, USA.
21Division of Translational Medicine and Human Genetics, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
22Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
23Department of Statistical Science, Duke University, Durham, NC, USA.
24Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address: alvaro.monteiro@moffitt.org.
Abstract
Carriers of BRCA1 and BRCA2 pathogenic variants are at a significantly elevated risk for several cancers. Widespread germline genetic testing has led to a significant increase in the detection of variants of uncertain significance (VUSs) in these genes. To assess variant pathogenicity, we curated, harmonized, and integrated functional data for 3,247 BRCA1 and 6,177 BRCA2 missense variants derived…
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