ArticleGenetics in medicine : official journal of the American College of Medical Genetics2022
Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 21 papers, 1 of them a synthesis that pooled it.
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21 citing papers in PubMed, 1 synthesis or guideline pooled it, 29 citations in OpenAlex.
- 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
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- Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management.Cancer medicine · 2024Article
- Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.American journal of human genetics · 2024Article
- Cancer Risks Associated WithJCO precision oncology · 2024Article
- Immunohistochemical Detection of the Expressed BRCA1 and BRCA2 Proteins in Microenvironment of Malignant Breast Cancerous Tissues Infected with Human Mammary Tumor Virus.Asian Pacific journal of cancer prevention : APJCP · 2023Article
- How the Analysis of the Pathogenetic Variants of DDR Genes Will Change the Management of Prostate Cancer Patients.International journal of molecular sciences · 2022Review
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Corrections and comments
- Erratum issued
Authors and funding
63 authors at 20 institutions in 18 countries.
Hongyan LiCancer Control and Population Science, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Christoph EngelInstitute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.
Miguel de la HoyaMolecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain.
Paolo PeterlongoGenome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
Drakoulis YannoukakosMolecular Diagnostics Laboratory, National Centre for Scientific Research "Demokritos", INRASTES Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, Athens, Greece.
Luca LivraghiMedical Oncology Unit, AZIENDA SOCIO SANITARIA TERRITORIALE PAPA GIOVANNI XXIII, Bergamo, Italy; University of Siena, Siena, Italy.
Paolo RadiceUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
Mads ThomassenDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Thomas V O HansenDepartment of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Anne-Marie GerdesDepartment of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Henriette R NielsenDepartment of Clinical Genetics Sygehus Lillebaelt, Vejle Hospital, Vejle, Denmark.
Sandrine M CaputoService de Génétique, Institut Curie, Paris, France; Paris Sciences and Lettres Research University, Paris, France.
Alberto ZambelliMedical Oncology Unit, AZIENDA SOCIO SANITARIA TERRITORIALE PAPA GIOVANNI XXIII, Bergamo, Italy.
Ake BorgDivisions of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Angela SolanoINBIOMED, Faculty of Medicine, University of Buenos Aires, CONICET and Genotyping Laboratory, Department of Clinical Chemistry, CEMIC, Buenos Aires, Argentina.
Abigail ThomasDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN.
Michael T ParsonsDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Antonis C AntoniouCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
Goska LeslieCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
Xin YangCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
Georgia Chenevix-TrenchDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Trinidad CaldesMolecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain.
Ava KwongCancer Genetics Centre, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong; Department of Surgery, LKS Faculty of Medicine,University of Hong Kong, Pok Fu Lam, Hong Kong.
Inge Søkilde PedersenMolecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark; Clinical Cancer Research Center and Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, The Faculty of Medicine, Aalborg University of Aalborg, Aalborg, Denmark.
Charlotte K LautrupClinical Cancer Research Center and Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, The Faculty of Medicine, Aalborg University of Aalborg, Aalborg, Denmark.
Esther M JohnDepartment of Epidemiology & Population Health and Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA.
Mary Beth TerryDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.
John L HopperCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
Melissa C SoutheyPrecision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Department of Clinical Pathology, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
Irene L AndrulisFred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Marc TischkowitzDepartment of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge, Cambridge, United Kingdom.
Ramunas JanaviciusDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania; State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
Susanne E BoonenDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Lone KroeldrupDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Liliana VarescoUnit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Ute HamannMolecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ana VegaFundación Pública galega Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.
Edenir I PalmeroMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil; National Cancer Institute, Rio de Janeiro, Brazil.
Judy GarberCenter for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA.
Marco MontagnaImmunology and Molecular Oncology Unit, IOV - Istituto Oncologico Veneto - IRCCS, Padova, Italy.
Christi J Van AsperenDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Lenka ForetovaDepartment of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
Mark H GreeneDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Tina SelkirkNorthShore University HealthSystem, University of Chicago, Evanston, IL.
Pal MollerDepartment of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal, Germany.
Amanda E TolandDepartment of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH.
Susan M DomchekBasser Center for BRCA, Abramson Cancer Center, Penn Medicine, University of Pennsylvania, Philadelphia, PA.
Paul A JamesParkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; The Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
Heather ThorneThe Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
Diana M EcclesFaculty of Medicine, University of Southampton, Southampton, United Kingdom.
Sarah M NielsenCenter for Clinical Cancer Genetics, The University of Chicago, Chicago, IL.
Siranoush ManoukianUnit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Barbara PasiniMedical Genetics Unit, Department of Medical Sciences, University of Torino, Torino, Italy.
Maria A CaligoSOD Genetica Molecolare, University Hospital, Pisa, Italy.
Conxi LazaroONCOBELL-IDIBELL-IDIBGI-IGTP, CIBERONC, Hereditary Cancer Program, Catalan Institute of Oncology, Barcelona, Spain.
Judy KirkFamilial Cancer Service, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney Medical School, University of Sydney, Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
Barbara WappenschmidtCenter for Hereditary Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine, University of Cologne, Cologne, Germany.
Amanda B SpurdleDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Fergus J CouchDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
Rita SchmutzlerCenter for Hereditary Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine, University of Cologne, Cologne, Germany.
David E GoldgarCancer Control and Population Science, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT. Electronic address: david.goldgar@hsc.utah.edu.
ENIGMA Consortium
CIMBA Consortium
The University of Melbourne · AUCentro de Investigación Biomédica en Red de Cáncer · ESOdense University Hospital · DKQIMR Berghofer Medical Research Institute · AUUniversity of Cambridge · GBAalborg University · DKFondazione IRCCS Istituto Nazionale dei Tumori · ITUniversity Hospital Cologne · DECambridge University Hospitals NHS Foundation Trust · GBCancer Genetics (United States) · USColumbia University · USCopenhagen University Hospital · DKFundación Pública Galega de Medicina Xenómica · ESGerman Cancer Research Center · DEHelios Universitätsklinikum Wuppertal · DEHuntsman Cancer Institute · USIFOM · ITInstitut Curie · FRInstitute of Nuclear & Radiological Sciences and Technology, Energy & SafetyInstituto Nacional do Câncer · BR
Funding
The Role of CHFR in Tumorigenesis and Paclitaxel-Sensitivity in Breast CancerP50CA116201 · NCI · MAYO CLINIC ROCHESTER · PI Fergus Joseph Couch · 2005 to 2026
$49.9MBreast Cancer Family Registry CohortUM1CA164920 · NCI · CANCER PREVENTION INSTIT OF CALIFORNIA · PI ANDRULIS, IRENE, BUYS, SAUNDRA S · 2012 to 2017
$12.7MRisk and penetrance of mutations from breast cancer testing panels.R01CA192393 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH, NATHANSON, KATHERINE L. · 2014 to 2018
$6.3MResolving the cancer relevance of predisposition gene mutationsR35CA253187 · NCI · MAYO CLINIC ROCHESTER · PI Fergus Joseph Couch · 2020 to 2026
$5.8MBRCA2 missense mutations and breast cancerR01CA116167 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH · 2007 to 2011
$3.0MThe contribution of RAD51C and RAD51D to breast and ovarian cancerR01CA225662 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH, WEROHA, SARAVUT · 2018 to 2024
$2.5MCancer Research UK 20861Cancer Research UK C12292/A20861NCI NIH HHS P50 CA116201NCI NIH HHS R01 CA116167NCI NIH HHS R01 CA192393NCI NIH HHS R01 CA225662NCI NIH HHS R35 CA253187NCI NIH HHS UM1 CA164920
Abstract
purposeGermline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.
methodsWe collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.
resultsEstimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs.
conclusionThese results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.
Indexed as
Breast NeoplasmsOvarian NeoplasmsBRCA1 ProteinBRCA2 ProteinFemaleGenes, BRCA1Genes, BRCA2Genetic Predisposition to DiseaseGenetic TestingGerm-Line MutationHumansMiddle AgedBRCA1 ProteinBRCA1 protein, humanBRCA2 ProteinBRCA2 protein, humanBRCA1BRCA2Cancer risksMissense variants
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