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      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Breast cancer risks associated with missense variants in breast cancer susceptibility genes

      research-article
      1 , 1 , 1 , 2 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 1 , 16 , 22 , 23 , 24 , 25 , 26 , 14 , 27 , 6 , 2 , NBCS Collaborators 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 1 , 17 , 38 , 39 , 40 , 41 , 42 , 13 , 43 , 6 , 25 , 44 , 45 , 38 , 46 , 47 , 6 , 48 , 49 , 50 , 7 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 38 , 59 , 60 , 41 , 42 , 61 , 62 , 63 , 64 , 5 , 65 , 66 , 67 , 42 , 68 , kConFab Investigators 69 , 70 , SGBCC Investigators 62 , 63 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 14 , 15 , 84 , 85 , 86 , 29 , 35 , 87 , 88 , 63 , 71 , 89 , 90 , 55 , 56 , 91 , 82 , 92 , 23 , 9 , 93 , 94 , 60 , 59 , 95 , 96 , 48 , 49 , 50 , 97 , 98 , 91 , 99 , 39 , 40 , 42 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 57 , 58 , 108 , 92 , 62 , 48 , 50 , 109 , 52 , 53 , 99 , 110 , 111 , 60 , 112 , 51 , 88 , 17 , 1 , 6 , 1 , 92 , 113 , 114 , 3 , 115 , 4 , 116 , 92 , 97 , 117 , 118 , 119 , 87 , 120 , 2 , 87 , 1 , 92 ,
      Genome Medicine
      BioMed Central
      Breast cancer, Genetic epidemiology, Risk prediction, Missense variants

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Protein 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.

          Methods

          We 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.

          Results

          The 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.

          Conclusions

          These 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.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13073-022-01052-8.

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          Most cited references32

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          The Ensembl Variant Effect Predictor

          The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.
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            • Record: found
            • Abstract: found
            • Article: not found

            A general framework for estimating the relative pathogenicity of human genetic variants

            Our capacity to sequence human genomes has exceeded our ability to interpret genetic variation. Current genomic annotations tend to exploit a single information type (e.g. conservation) and/or are restricted in scope (e.g. to missense changes). Here, we describe Combined Annotation Dependent Depletion (CADD), a framework that objectively integrates many diverse annotations into a single, quantitative score. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human derived alleles from 14.7 million simulated variants. We pre-compute “C-scores” for all 8.6 billion possible human single nucleotide variants and enable scoring of short insertions/deletions. C-scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects, and complex trait associations, and highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious, and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current annotation.
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              • Record: found
              • Abstract: found
              • Article: not found

              REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants.

              The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10(-12)) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.
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                Author and article information

                Contributors
                dfe20@medschl.cam.ac.uk
                Journal
                Genome Med
                Genome Med
                Genome Medicine
                BioMed Central (London )
                1756-994X
                18 May 2022
                18 May 2022
                2022
                : 14
                : 51
                Affiliations
                [1 ]GRID grid.5335.0, ISNI 0000000121885934, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, , University of Cambridge, ; Cambridge, CB1 8RN UK
                [2 ]GRID grid.1049.c, ISNI 0000 0001 2294 1395, Department of Genetics and Computational Biology, , QIMR Berghofer Medical Research Institute, ; Brisbane, QLD 4006 Australia
                [3 ]GRID grid.7719.8, ISNI 0000 0000 8700 1153, Human Cancer Genetics Programme, , Spanish National Cancer Research Centre (CNIO), ; 28029 Madrid, Spain
                [4 ]GRID grid.432909.5, Bio-Prodict, ; Nijmegen, The Netherlands
                [5 ]GRID grid.430814.a, ISNI 0000 0001 0674 1393, Family Cancer Clinic, , The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, ; Amsterdam, 1066 CX The Netherlands
                [6 ]GRID grid.48336.3a, ISNI 0000 0004 1936 8075, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, , National Cancer Institute, National Institutes of Health, ; Bethesda, MD 20850 USA
                [7 ]GRID grid.250674.2, ISNI 0000 0004 0626 6184, Fred A. Litwin Center for Cancer Genetics, , Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, ; Toronto, ON M5G 1X5 Canada
                [8 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Molecular Genetics, , University of Toronto, ; Toronto, ON M5S 1A8 Canada
                [9 ]GRID grid.9668.1, ISNI 0000 0001 0726 2490, Translational Cancer Research Area, , University of Eastern Finland, ; 70210 Kuopio, Finland
                [10 ]GRID grid.9668.1, ISNI 0000 0001 0726 2490, Institute of Clinical Medicine, Oncology, , University of Eastern Finland, ; 70210 Kuopio, Finland
                [11 ]GRID grid.410705.7, ISNI 0000 0004 0628 207X, Department of Oncology, Cancer Center, , Kuopio University Hospital, ; 70210 Kuopio, Finland
                [12 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Medical Biometry and Epidemiology, , University Medical Center Hamburg-Eppendorf, ; 20246 Hamburg, Germany
                [13 ]GRID grid.411668.c, ISNI 0000 0000 9935 6525, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, , University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), ; 91054 Erlangen, Germany
                [14 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Division of Cancer Epidemiology, , German Cancer Research Center (DKFZ), ; 69120 Heidelberg, Germany
                [15 ]GRID grid.429129.5, Institute of Biochemistry and Genetics, , Ufa Federal Research Centre of the Russian Academy of Sciences, ; Ufa, 450054 Russia
                [16 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Radiation Oncology, , Hannover Medical School, ; 30625 Hannover, Germany
                [17 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Gynaecology Research Unit, , Hannover Medical School, ; 30625 Hannover, Germany
                [18 ]GRID grid.477553.7, ISNI 0000 0004 0516 9294, N.N. Alexandrov Research Institute of Oncology and Medical Radiology, ; 223040 Minsk, Belarus
                [19 ]GRID grid.4973.9, ISNI 0000 0004 0646 7373, Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, ; 2730 Herlev, Denmark
                [20 ]GRID grid.4973.9, ISNI 0000 0004 0646 7373, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, , Copenhagen University Hospital, ; 2730 Herlev, Denmark
                [21 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Faculty of Health and Medical Sciences, , University of Copenhagen, ; 2200 Copenhagen, Denmark
                [22 ]GRID grid.412166.6, ISNI 0000 0001 2111 4451, Medical Faculty, , Universidad de La Sabana, ; 140013 Bogota, Colombia
                [23 ]GRID grid.223827.e, ISNI 0000 0001 2193 0096, Department of Internal Medicine and Huntsman Cancer Institute, , University of Utah, ; Salt Lake City, UT 84112 USA
                [24 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, , The University of Edinburgh, Western General Hospital, ; Edinburgh, EH4 2XU UK
                [25 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Usher Institute of Population Health Sciences and Informatics, , The University of Edinburgh, ; Edinburgh, EH16 4UX UK
                [26 ]Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312 Vigo, Spain
                [27 ]GRID grid.412315.0, Cancer Epidemiology Group, , University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, ; 20246 Hamburg, Germany
                [28 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Cancer Genetics, Institute for Cancer Research, , Oslo University Hospital-Radiumhospitalet, ; 0379 Oslo, Norway
                [29 ]GRID grid.5510.1, ISNI 0000 0004 1936 8921, Institute of Clinical Medicine, Faculty of Medicine, , University of Oslo, ; 0450 Oslo, Norway
                [30 ]GRID grid.459157.b, ISNI 0000 0004 0389 7802, Department of Research, , Vestre Viken Hospital, ; 3019 Drammen, Norway
                [31 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Tumor Biology, Institute for Cancer Research, , Oslo University Hospital-Radiumhospitalet, ; 0379 Oslo, Norway
                [32 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Oncology, Division of Surgery, Cancer and Transplantation Medicine, , Oslo University Hospital-Radiumhospitalet, ; 0379 Oslo, Norway
                [33 ]GRID grid.411279.8, ISNI 0000 0000 9637 455X, Department of Oncology, , Akershus University Hospital, ; 1478 Lørenskog, Norway
                [34 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Breast Cancer Research Consortium, Oslo University Hospital, ; 0379 Oslo, Norway
                [35 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Medical Genetics, , Oslo University Hospital and University of Oslo, ; 0379 Oslo, Norway
                [36 ]GRID grid.10919.30, ISNI 0000000122595234, Department of Community Medicine, , The Arctic University of Norway, ; 9037 Tromsø, Norway
                [37 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Clinical Genetics, , Erasmus University Medical Center, ; Rotterdam, 3015 CN The Netherlands
                [38 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Medical Epidemiology and Biostatistics, , Karolinska Institutet, ; 171 65 Stockholm, Sweden
                [39 ]GRID grid.5379.8, ISNI 0000000121662407, Division 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
                [40 ]GRID grid.416523.7, ISNI 0000 0004 0641 2620, North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, , St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, ; Manchester, M13 9WL UK
                [41 ]GRID grid.417286.e, ISNI 0000 0004 0422 2524, Nightingale & Genesis Prevention Centre, , Wythenshawe Hospital, Manchester University NHS Foundation Trust, ; Manchester, M23 9LT UK
                [42 ]GRID grid.498924.a, ISNI 0000 0004 0430 9101, NIHR Manchester Biomedical Research Centre, , Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, ; Manchester, M13 9WL UK
                [43 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, , University of California at Los Angeles, ; Los Angeles, CA 90095 USA
                [44 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Cancer Research UK Edinburgh Centre, , The University of Edinburgh, ; Edinburgh, EH4 2XR UK
                [45 ]GRID grid.4973.9, ISNI 0000 0004 0646 7373, Department of Breast Surgery, Herlev and Gentofte Hospital, , Copenhagen University Hospital, ; 2730 Herlev, Denmark
                [46 ]GRID grid.411048.8, ISNI 0000 0000 8816 6945, Fundación 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
                [47 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Moores Cancer Center, , University of California San Diego, ; La Jolla, CA 92037 USA
                [48 ]GRID grid.3263.4, ISNI 0000 0001 1482 3639, Cancer Epidemiology Division, , Cancer Council Victoria, ; Melbourne, VIC 3004 Australia
                [49 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, , The University of Melbourne, ; Melbourne, VIC 3010 Australia
                [50 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Precision Medicine, School of Clinical Sciences at Monash Health, , Monash University, ; Clayton, VIC 3168 Australia
                [51 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Team “Exposome and Heredity”, , CESP, Inserm, Gustave Roussy, University Paris-Saclay, UVSQ, ; Villejuif, France
                [52 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), ; 69120 Heidelberg, Germany
                [53 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Molecular Biology of Breast Cancer, , University Womens Clinic Heidelberg, University of Heidelberg, ; 69120 Heidelberg, Germany
                [54 ]GRID grid.4567.0, ISNI 0000 0004 0483 2525, Institute of Diabetes Research, , Helmholtz Zentrum München, German Research Center for Environmental Health, ; 85764 Neuherberg, Germany
                [55 ]GRID grid.417705.0, ISNI 0000 0004 0609 0940, Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, ; 2371 Nicosia, Cyprus
                [56 ]GRID grid.417705.0, ISNI 0000 0004 0609 0940, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, ; 2371 Nicosia, Cyprus
                [57 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Center for Familial Breast and Ovarian Cancer, , Faculty of Medicine and University Hospital Cologne, University of Cologne, ; 50937 Cologne, Germany
                [58 ]GRID grid.411097.a, ISNI 0000 0000 8852 305X, Center for Integrated Oncology (CIO), Faculty of Medicine, , University Hospital Cologne, University of Cologne, ; 50937 Cologne, Germany
                [59 ]GRID grid.416648.9, ISNI 0000 0000 8986 2221, Department of Oncology, ; 118 83 Södersjukhuset, Stockholm, Sweden
                [60 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), ; 69120 Heidelberg, Germany
                [61 ]GRID grid.5379.8, ISNI 0000000121662407, Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, , University of Manchester, Manchester Academic Health Science Centre, ; Manchester, M13 9PT UK
                [62 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, Saw Swee Hock School of Public Health, , National University of Singapore and National University Health System, ; Singapore, 117549 Singapore
                [63 ]GRID grid.410759.e, ISNI 0000 0004 0451 6143, Department of Surgery, , National University Health System, ; Singapore, 119228 Singapore
                [64 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, Department of Surgery, , Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, ; Singapore, 119228 Singapore
                [65 ]GRID grid.508717.c, ISNI 0000 0004 0637 3764, Department of Medical Oncology, , Erasmus MC Cancer Institute, ; Rotterdam, 3015 GD The Netherlands
                [66 ]GRID grid.502798.1, ISNI 0000 0004 0561 903X, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, ; 70376 Stuttgart, Germany
                [67 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, University of Tübingen, ; 72074 Tübingen, Germany
                [68 ]GRID grid.5379.8, ISNI 0000000121662407, Division of Cancer Sciences, , University of Manchester, ; Manchester, M13 9PL UK
                [69 ]GRID grid.1055.1, ISNI 0000000403978434, Research Department, , Peter MacCallum Cancer Center, ; Melbourne, VIC 3000 Australia
                [70 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Oncology, , Sir Peter MacCallum, The University of Melbourne, ; Melbourne, VIC 3000 Australia
                [71 ]GRID grid.418377.e, ISNI 0000 0004 0620 715X, Human Genetics Division, , Genome Institute of Singapore, ; Singapore, 138672 Singapore
                [72 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, Department of Medicine, , Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, ; Singapore, 119077 Singapore
                [73 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Cancer Genetics Service, , National Cancer Centre, ; Singapore, 169610 Singapore
                [74 ]GRID grid.414963.d, ISNI 0000 0000 8958 3388, Breast Department, , KK Women’s and Children’s Hospital, ; Singapore, 229899 Singapore
                [75 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, SingHealth Duke-NUS Breast Centre, ; Singapore, 168753 Singapore
                [76 ]GRID grid.240988.f, ISNI 0000 0001 0298 8161, Department of General Surgery, , Tan Tock Seng Hospital, ; Singapore, 308433 Singapore
                [77 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Division of Surgical Oncology, , National Cancer Centre, ; Singapore, 169610 Singapore
                [78 ]GRID grid.163555.1, ISNI 0000 0000 9486 5048, Department of General Surgery, , Singapore General Hospital, ; Singapore, 169608 Singapore
                [79 ]GRID grid.413815.a, ISNI 0000 0004 0469 9373, Division of Breast Surgery, Department of General Surgery, , Changi General Hospital, ; Singapore, 529889 Singapore
                [80 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Division of Radiation Oncology, , National Cancer Centre, ; Singapore, 169610 Singapore
                [81 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Division of Medical Oncology, , National Cancer Centre, ; Singapore, 169610 Singapore
                [82 ]GRID grid.107950.a, ISNI 0000 0001 1411 4349, Department of Genetics and Pathology, , Pomeranian Medical University, ; 71-252 Szczecin, Poland
                [83 ]GRID grid.107950.a, ISNI 0000 0001 1411 4349, Independent Laboratory of Molecular Biology and Genetic Diagnostics, , Pomeranian Medical University, ; 71-252 Szczecin, Poland
                [84 ]GRID grid.77269.3d, ISNI 0000 0001 1015 7624, Department of Genetics and Fundamental Medicine, , Bashkir State University, ; Ufa, 450000 Russia
                [85 ]Department of Surgery, Daerim Saint Mary’s Hospital, Seoul, 07442 Korea
                [86 ]Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, 53113 Bonn, Germany
                [87 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Human Genetics, , Leiden University Medical Center, ; Leiden, 2333 ZA The Netherlands
                [88 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Clinical Genetics, , Leiden University Medical Center, ; Leiden, 2333 ZA The Netherlands
                [89 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Molecular Medicine and Surgery, , Karolinska Institutet, ; 171 76 Stockholm, Sweden
                [90 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Department of Clinical Genetics, , Karolinska University Hospital, ; 171 76 Stockholm, Sweden
                [91 ]GRID grid.5379.8, ISNI 0000000121662407, Division 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
                [92 ]GRID grid.5335.0, ISNI 0000000121885934, Centre for Cancer Genetic Epidemiology, Department of Oncology, , University of Cambridge, ; Cambridge, CB1 8RN UK
                [93 ]GRID grid.9668.1, ISNI 0000 0001 0726 2490, Institute of Clinical Medicine, Pathology and Forensic Medicine, , University of Eastern Finland, ; 70210 Kuopio, Finland
                [94 ]GRID grid.410705.7, ISNI 0000 0004 0628 207X, Biobank of Eastern Finland, , Kuopio University Hospital, ; Kuopio, Finland
                [95 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Clinical Science and Education, , Södersjukhuset, Karolinska Institutet, ; 118 83 Stockholm, Sweden
                [96 ]GRID grid.412481.a, ISNI 0000 0004 0576 5678, Department of Medical Oncology, , University Hospital of Heraklion, ; 711 10 Heraklion, Greece
                [97 ]GRID grid.10347.31, ISNI 0000 0001 2308 5949, Breast Cancer Research Unit, Faculty of Medicine, , University Malaya Cancer Research Institute, University of Malaya, ; 50603 Kuala Lumpur, Malaysia
                [98 ]GRID grid.10347.31, ISNI 0000 0001 2308 5949, Department of Surgery, Faculty of Medicine, , University of Malaya, ; 50603 Kuala Lumpur, Malaysia
                [99 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Department of Obstetrics and Gynecology, , Helsinki University Hospital, University of Helsinki, ; 00290 Helsinki, Finland
                [100 ]GRID grid.4830.f, ISNI 0000 0004 0407 1981, Department of Genetics, , University Medical Center Groningen, University Groningen, ; Groningen, 9713 GZ The Netherlands
                [101 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Department of Preventive Medicine, , Seoul National University College of Medicine, ; Seoul, 03080 Korea
                [102 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Convergence Graduate Program in Innovative Medical Science, , Seoul National University College of Medicine, ; Seoul, 03080 South Korea
                [103 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Cancer Research Institute, Seoul National University, ; Seoul, 03080 Korea
                [104 ]GRID grid.7678.e, ISNI 0000 0004 1757 7797, Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, ; 20139 Milan, Italy
                [105 ]GRID grid.417893.0, ISNI 0000 0001 0807 2568, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, , Fondazione IRCCS Istituto Nazionale Dei Tumori (INT), ; 20133 Milan, Italy
                [106 ]GRID grid.411299.6, Department of Oncology, , University Hospital of Larissa, ; 411 10 Larissa, Greece
                [107 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, , Guy’s Campus, King’s College London, ; London, UK
                [108 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Center for Molecular Medicine Cologne (CMMC), , Faculty of Medicine and University Hospital Cologne, University of Cologne, ; 50931 Cologne, Germany
                [109 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Clinical Pathology, , The University of Melbourne, ; Melbourne, VIC 3010 Australia
                [110 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Institute of Cancer and Genomic Sciences, , University of Birmingham, ; Birmingham, B15 2TT UK
                [111 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, , University of Oxford, ; Oxford, OX3 7BN UK
                [112 ]GRID grid.41312.35, ISNI 0000 0001 1033 6040, Institute of Human Genetics, , Pontificia Universidad Javeriana, ; 110231 Bogota, Colombia
                [113 ]GRID grid.430814.a, ISNI 0000 0001 0674 1393, Division of Molecular Pathology, , The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, ; Amsterdam, 1066 CX The Netherlands
                [114 ]GRID grid.430814.a, ISNI 0000 0001 0674 1393, Division of Psychosocial Research and Epidemiology, , The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, ; Amsterdam, 1066 CX The Netherlands
                [115 ]GRID grid.452372.5, ISNI 0000 0004 1791 1185, Biomedical Network On Rare Diseases (CIBERER), ; 28029 Madrid, Spain
                [116 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Centre for Molecular and Biomolecular Informatics (CMBI), , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [117 ]GRID grid.507182.9, ISNI 0000 0004 1786 3427, Breast Cancer Research Programme, , Cancer Research Malaysia, ; Subang Jaya, 47500 Selangor, Malaysia
                [118 ]GRID grid.4514.4, ISNI 0000 0001 0930 2361, Division of Oncology and Pathology, Department of Clinical Sciences Lund, , Lund University, ; 22381 Lund, Sweden
                [119 ]GRID grid.411068.a, ISNI 0000 0001 0671 5785, Molecular Oncology Laboratory, , Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), ; 28040 Madrid, Spain
                [120 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Pathology, , Leiden University Medical Center, ; Leiden, 2333 ZA The Netherlands
                Article
                1052
                10.1186/s13073-022-01052-8
                9116026
                33471991
                0b8fee12-4d3b-4671-9af6-82b4e7948b66
                © The Author(s) 2022

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                History
                : 20 August 2021
                : 4 May 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100007601, Horizon 2020;
                Award ID: 634935
                Award ID: 633784
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: v203477/Z/16/Z
                Funded by: FundRef http://dx.doi.org/10.13039/501100000289, Cancer Research UK;
                Award ID: C1287/A16563
                Categories
                Research
                Custom metadata
                © The Author(s) 2022

                Molecular medicine
                breast cancer,genetic epidemiology,risk prediction,missense variants
                Molecular medicine
                breast cancer, genetic epidemiology, risk prediction, missense variants

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