BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

2nd Department of Pediatrics Semmelweis University Budapest Hungary

Biotech Research and Innovation Centre Copenhagen Denmark; Finsen Laboratory Rigshospitalet University of Copenhagen Copenhagen Denmark; European Molecular Biology Laboratory Genome Biology Unit Heidelberg Germany

Broad Institute of Harvard and Massachusetts Institute of Technology Cambridge MA USA; Department of Neurology Boston Children's Hospital and Harvard Medical School Boston MA USA

Cancer Registry of Norway Oslo Norway

Cnopf'sche Kinderklinik Nuremberg Germany

Comprehensive Cancer Center Mainfranken Würzburg Germany; Department of Neuropathology Institute of Pathology University of Würzburg Würzburg Germany

Danish Cancer Society Research Center Copenhagen Denmark

Data Management Facility German Cancer Research Center Heidelberg Germany

Department of Anatomical and Cellular Pathology The Chinese University of Hong Kong Hong Kong Special Administrative Region China

Department of Biochemistry and Molecular Biology Cumming School of Medicine University of Calgary Calgary AB Canada; Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto ON Canada

Department of Children and Adolescents Oncology Gustave Roussy Cancer Campus Villejuif France

Department of Computational Biology St Jude Children's Research Hospital Memphis TN USA

Department of Epidemiology and Public Health Swiss Tropical and Public Health Institute Basel Switzerland; Swiss Tropical and Public Health Institute University of Basel Basel Switzerland

Department of Neurology Boston Children's Hospital and Harvard Medical School Boston MA USA

Department of Neuropathology Burdenko Neurosurgical Institute Moscow Russia

Department of Neuropathology Heidelberg University Hospital Heidelberg Germany; Clinical Cooperation Unit Neuropathology German Cancer Research Center Heidelberg Germany

Department of Neuropathology Sainte Anne Hospital Paris France

Department of Neurosurgery Asan Medical Center Seoul South Korea

Department of Neurosurgery University of Utah School of Medicine Salt Lake City UT USA

Department of Oncology and Cancer Research UK Cambridge Institute University of Cambridge Cambridge UK

Department of Oncology St Jude Children's Research Hospital Memphis TN USA

Department of Paediatric Oncology Lady Cilento Children's Hospital South Brisbane QLD Australia

Department of Paediatric Oncology Sydney Children's Hospital Sydney NSW Australia

Department of Paediatric Oncology The Children's Hospital at Westmead Sydney NSW Australia

Department of Paediatric Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic; Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Pathology and Laboratory Medicine Department of Oncology and Department of Clinical Neurosciences University of Calgary Calgary AB Canada

Department of Pathology Children's Memorial Health Institute Warsaw Poland

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine University Hospital Motol Charles University Prague Czech Republic

Department of Pediatric Hematology and Oncology Children's Hospitals and Clinics of Minnesota Minneapolis MN USA

Department of Pediatric Hematology and Oncology Heidelberg University Hospital Heidelberg Germany; Clinical Cooperation Unit Pediatric Oncology German Cancer Consortium Heidelberg Germany; Hopp Children's Cancer Center at the NCT Heidelberg Heidelberg Germany

Department of Pediatric Hematology and Oncology Heidelberg University Hospital Heidelberg Germany; Division of Pediatric Neurooncology German Cancer Consortium Heidelberg Germany; Hopp Children's Cancer Center at the NCT Heidelberg Heidelberg Germany

Department of Pediatric Hematology and Oncology Texas Children's Hospital Houston TX USA

Department of Pediatric Hematology and Oncology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Pediatric Hematology and Oncology University Medical Center Hamburg Eppendorf Hamburg Germany; Klinik für Pädiatrie mS Onkologie und Hämatologie Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Berlin Germany

Department of Pediatric Medicine Oslo University Hospital Oslo Norway; Institute of Clinical Medicine University of Oslo Oslo Norway; Cancer Registry of Norway Oslo Norway

Department of Pediatric Oncology University Children's Hospital Zurich University of Zurich Zurich Switzerland

Department of Pediatrics Aflac Cancer and Blood Disorders Center Emory University School of Medicine Atlanta GA USA

Department of Pediatrics McGill University Montreal QC Canada

Department of Pediatrics University of Gothenburg The Queen Silvia Children's Hospital Gothenburg Sweden

Departments of Genetics and Biomedical Data Science Stanford University School of Medicine Stanford CA USA

Division of Haematology Oncology The Hospital for Sick Children Toronto ON Canada; Department of Pediatrics University of Toronto Toronto ON Canada

Division of Molecular Genetics German Cancer Consortium Heidelberg Germany

Division of Molecular Genetics German Cancer Research Center Heidelberg Germany

Division of Neuropathology Department of Pathology and Helen Diller Family Comprehensive Cancer Center University of California San Francisco CA USA

Division of Neurosurgery The Hospital for Sick Children Toronto ON Canada

Division of Pediatric Hematology Oncology University of Texas Southwestern Medical School Dallas TX USA

Division of Pediatric Neurooncology German Cancer Consortium Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Consortium Heidelberg Germany; Department of Developmental Neurobiology St Jude Children's Research Hospital Memphis TN USA

Division of Pediatric Neurooncology German Cancer Consortium Heidelberg Germany; Hopp Children's Cancer Center at the NCT Heidelberg Heidelberg Germany

Division of Theoretical Bioinformatics German Cancer Research Center Heidelberg Germany

Division of Theoretical Bioinformatics German Cancer Research Center Heidelberg Germany; Division of Applied Bioinformatics German Cancer Research Center Heidelberg Germany

European Molecular Biology Laboratory Genome Biology Unit Heidelberg Germany

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Human Genetics Heidelberg University Heidelberg Germany

Institute of Neuropathology University Hospital Basel Basel Switzerland

Klinik für Pädiatrie mS Onkologie und Hämatologie Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Berlin Germany

Michael Smith Genome Sciences Centre BC Cancer Agency Vancouver BC Canada

Oncology Clinic Finsen Centre Rigshospitalet University of Copenhagen Copenhagen Denmark; Unit of Survivorship Copenhagen Denmark

Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

Pediatric Oncology and Hematology Pediatrics 3 University Hospital of Essen Essen Germany

Section of Environment and Radiation International Agency for Research on Cancer Lyon France

Swiss Childhood Cancer Registry Institute of Social and Preventive Medicine University of Bern Bern Switzerland

University Health Network Toronto General Hospital Toronto ON Canada

Valley Children's Hospital Madera CA USA

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