ArticleGenome medicine2022
Breast cancer risks associated with missense variants in breast cancer susceptibility genes.
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Article in Genome medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 3 of them syntheses that pooled it.
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42citing papers in PubMed, 3 pooled it
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42 citing papers in PubMed, 3 syntheses or guidelines pooled it, 54 citations in OpenAlex.
- EMQN best practice guidelines for genetic testing in hereditary breast and ovarian cancer.European journal of human genetics : EJHG · 2024Guideline
- Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).Genetics in medicine : official journal of the American College of Medical Genetics · 2023Guideline
- ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Pooled it
- Clinical impact of ENIGMA-based variant reclassification on genotype-phenotype analyses in BRCA1- and BRCA2-associated hereditary breast and ovarian cancer.Breast cancer (Tokyo, Japan) · 2026Article
- Article
- The contribution of rare germline variants to the immune landscape of breast cancer.Genome medicine · 2026Article
- Co-Pathogenic Role of BRCA1 and OBSCN Deletions in Chinese Familial Breast Cancer: A Case Report.The American journal of case reports · 2026Article
- BARD1 recognizes pre-rRNA for DNA damage repair and rRNA biogenesis.The Journal of biological chemistry · 2026Article
- Review
- Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk.Nature communications · 2026Article
- Clinically interpretable deep learning for breast cancer missense variant pathogenicity prediction.Frontiers in bioinformatics · 2026Article
- Low Frequency of Pathogenic Variants in BRCA1 Exons 11/20 and BRCA2 Exon 11 Suggests Divergent Mutational Hotspots in Sudanese Breast Cancer Patients: A Case-Control Study.Breast cancer : basic and clinical research · 2026Article
- Genomic Ascertainment of CHEK2-Related Cancer Predisposition.JAMA network open · 2025Article
- Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.Molecular neurodegeneration · 2025Article
- Damage-induced phosphorylation of BRC-1/BRD-1 in meiosis preserves germline integrity.Nucleic acids research · 2025Article
- Whole exome sequencing identifies FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer in Hispanic/Latina women.Nature communications · 2025Article
- Associations betweenJournal of medical genetics · 2025Article
- Association of gene variant type and location with breast cancer risk in the general population.Annals of oncology : official journal of the European Society for Medical Oncology · 2025Article
- Multi-dimensional annotation of porcine variants using genomic and epigenomic features in pigs.BMC biology · 2025Article
- Understanding how gene-disease relationships can impact clinical utility: adaptations and challenges in hereditary cancer testing.Genome medicine · 2025Article
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Authors and funding
109 authors at 20 institutions in 22 countries.
Leila DorlingCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
Sara CarvalhoCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
Jamie AllenCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
Michael T ParsonsDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Cristina FortunoDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Anna González-NeiraHuman Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.
Stephan M HeijlBio-Prodict, Nijmegen, The Netherlands.
Muriel A AdankFamily Cancer Clinic, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
Thomas U AhearnDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
Irene L AndrulisFred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
Päivi AuvinenTranslational Cancer Research Area, University of Eastern Finland, 70210, Kuopio, Finland.
Heiko BecherInstitute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Matthias W BeckmannDepartment of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany.
Sabine BehrensDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Marina BermishevaInstitute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russia.
Natalia V BogdanovaDepartment of Radiation Oncology, Hannover Medical School, 30625, Hannover, Germany.
Stig E BojesenCopenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
Manjeet K BollaCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
Michael BremerDepartment of Radiation Oncology, Hannover Medical School, 30625, Hannover, Germany.
Ignacio BricenoMedical Faculty, Universidad de La Sabana, 140013, Bogota, Colombia.
Nicola J CampDepartment of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
Archie CampbellCentre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, The University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
Jose E CastelaoOncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312, Vigo, Spain.
Jenny Chang-ClaudeDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Stephen J ChanockDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
Georgia Chenevix-TrenchDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
NBCS Collaborators
J Margriet ColléeDepartment of Clinical Genetics, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
Kamila CzeneDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65, Stockholm, Sweden.
Joe DennisCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
Thilo DörkGynaecology Research Unit, Hannover Medical School, 30625, Hannover, Germany.
Mikael ErikssonDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65, Stockholm, Sweden.
D Gareth EvansDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
Peter A FaschingDepartment of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany.
Jonine FigueroaDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
Henrik FlygerDepartment of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
Marike GabrielsonDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65, Stockholm, Sweden.
Manuela Gago-DominguezFundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, , 15706, Santiago de Compostela, Spain.
Montserrat García-ClosasDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
Graham G GilesCancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
Gord GlendonFred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
Pascal GuénelTeam "Exposome and Heredity", CESP, Inserm, Gustave Roussy, University Paris-Saclay, UVSQ, Villejuif, France.
Melanie GündertMolecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Andreas HadjisavvasCancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 2371, Nicosia, Cyprus.
Eric HahnenCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
Per HallDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65, Stockholm, Sweden.
Ute HamannMolecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Elaine F HarknessNightingale & Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, M23 9LT, UK.
Mikael HartmanSaw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, 117549, Singapore.
Frans B L HogervorstFamily Cancer Clinic, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
Antoinette HollestelleDepartment of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 GD, The Netherlands.
Reiner HoppeDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376, Stuttgart, Germany.
Anthony HowellNIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
kConFab Investigators
SGBCC Investigators
Anna JakubowskaDepartment of Genetics and Pathology, Pomeranian Medical University, 71-252, Szczecin, Poland.
Audrey JungDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Elza KhusnutdinovaInstitute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russia.
Sung-Won KimDepartment of Surgery, Daerim Saint Mary's Hospital, Seoul, 07442, Korea.
Yon-Dschun KoDepartment of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, 53113, Bonn, Germany.
Vessela N KristensenInstitute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450, Oslo, Norway.
Inge M M LakemanDepartment of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
Jingmei LiDepartment of Surgery, National University Health System, Singapore, 119228, Singapore.
Annika LindblomDepartment of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden.
Maria A LoizidouCancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 2371, Nicosia, Cyprus.
Artitaya LophatananonDivision of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, UK.
Jan LubińskiDepartment of Genetics and Pathology, Pomeranian Medical University, 71-252, Szczecin, Poland.
Craig LuccariniCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
Michael J MadsenDepartment of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
Arto MannermaaTranslational Cancer Research Area, University of Eastern Finland, 70210, Kuopio, Finland.
Mehdi ManoochehriMolecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Sara MargolinDepartment of Oncology, 118 83, Södersjukhuset, Stockholm, Sweden.
Dimitrios MavroudisDepartment of Medical Oncology, University Hospital of Heraklion, 711 10, Heraklion, Greece.
Roger L MilneCancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
Nur Aishah Mohd TaibBreast Cancer Research Unit, Faculty of Medicine, University Malaya Cancer Research Institute, University of Malaya, 50603, Kuala Lumpur, Malaysia.
Kenneth MuirDivision of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, UK.
Heli NevanlinnaDepartment of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland.
William G NewmanDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
Jan C OosterwijkDepartment of Genetics, University Medical Center Groningen, University Groningen, Groningen, 9713 GZ, The Netherlands.
Sue K ParkDepartment of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.
Paolo PeterlongoGenome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, 20139, Milan, Italy.
Paolo RadiceUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT), 20133, Milan, Italy.
Emmanouil SaloustrosDepartment of Oncology, University Hospital of Larissa, 411 10, Larissa, Greece.
Elinor J SawyerSchool of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
Rita K SchmutzlerCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
Mitul ShahCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
Xueling SimSaw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, 117549, Singapore.
Melissa C SoutheyCancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
Harald SurowyMolecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Maija SuvantoDepartment of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland.
Ian TomlinsonInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
Diana TorresMolecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Thérèse TruongTeam "Exposome and Heredity", CESP, Inserm, Gustave Roussy, University Paris-Saclay, UVSQ, Villejuif, France.
Christi J van AsperenDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
Regina WaltesGynaecology Research Unit, Hannover Medical School, 30625, Hannover, Germany.
Qin WangCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
Xiaohong R YangDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
Paul D P PharoahCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
Marjanka K SchmidtDivision of Molecular Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
Javier BenitezHuman Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.
Bas VrolingBio-Prodict, Nijmegen, The Netherlands.
Alison M DunningCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
Soo Hwang TeoBreast Cancer Research Unit, Faculty of Medicine, University Malaya Cancer Research Institute, University of Malaya, 50603, Kuala Lumpur, Malaysia.
Anders KvistDivision of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 22381, Lund, Sweden.
Miguel de la HoyaMolecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), 28040, Madrid, Spain.
Peter DevileeDepartment of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
Amanda B SpurdleDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Maaike P G VreeswijkDepartment of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
Douglas F EastonCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. dfe20@medschl.cam.ac.uk.
University of Cambridge · GBGerman Cancer Research Center · DEManchester Academic Health Science Centre · GBNational Institutes of Health · USLeiden University Medical Center · NLQIMR Berghofer Medical Research Institute · AUUniversity of Cologne · DEUniversity of Helsinki · FIKarolinska Institutet · SEMount Sinai Hospital · CANational University of Singapore · SGUniversity of Eastern Finland · FIUniversity of Utah · USCentre for Human Genetics · GBErasmus MC · NLInserm · FRMedizinische Hochschule Hannover · DEOslo University Hospital · NORadboud University Nijmegen · NLThe Netherlands Cancer Institute · NL
Funding
Hormone-Related CancersZIACP010126 · NCI · DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS · PI GIERACH, GRETCHEN · 2009 to 2025
$103.5MCancer Research UK 16563Cancer Research UK C1287/A16563Wellcome Trust 203477/Z/16/ZWellcome Trust v203477/Z/16/Z
Abstract
backgroundProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.
methodsWe analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.
resultsThe most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.
conclusionsThese results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
Indexed as
Breast NeoplasmsCase-Control StudiesFemaleGenetic Predisposition to DiseaseHumansMutation, MissenseBreast cancerGenetic epidemiologyMissense variantsRisk prediction
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