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      Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

      1 , 2 , 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 22 , 23 , 31 , 32 , 10 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 19 , 11 , 41 , 11 , 42 , 3 , 43 , 44
      Nature genetics
      Springer Science and Business Media LLC

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          Abstract

          The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

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          Most cited references43

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          Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

          Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. (c) 2008 Wiley-Liss, Inc.
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            Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

            Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed. Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias. Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations. MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.
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              Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker.

              Unambiguous and correct sequence variant descriptions are of utmost importance, not in the least since mistakes and uncertainties may lead to undesired errors in clinical diagnosis. We developed the Mutation Analyzer (Mutalyzer) sequence variation nomenclature checker (www.lovd.nl/mutalyzer; last accessed 13 September 2007) for automated analysis and correction of sequence variant descriptions using reference sequences from any organism. Mutalyzer handles most variation types: substitution, deletion, duplication, insertion, indel, and splice-site changes following current recommendations of the Human Genome Variation Society (HGVS). Input is a GenBank accession number or an uploaded reference sequence file in GenBank format with user-modified annotation, an HGNC gene symbol, and the variant (single or in a batch file). Mutalyzer generates variant descriptions at DNA level, the level of all annotated transcripts and the deduced outcome at protein level. To validate Mutalyzer's performance and to investigate the sequence variant description quality in locus-specific mutation databases (LSDBs), more than 11,000 variants in the PAH, BIC BRCA2, and HbVar databases were analyzed, showing that 87%, 25%, and 38%, respectively, were error-free and following the recommendations. Low recognition rates in BIC and HbVar (38% and 51%, respectively) were due to lack of a well-annotated genomic reference sequence (HbVar) or noncompliance to the guidelines (BRCA2). Provided with well-annotated genomic reference sequences, Mutalyzer is very effective for the curation of newly discovered sequence variation descriptions and existing LSDB data. Mutalyzer will be linked to the Leiden Open source Variation Database (LOVD) (www.LOVD.nl; last accessed 13 September 2007) and is the first module of a sequence variant effect prediction package. (c) 2007 Wiley-Liss, Inc.
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                Author and article information

                Journal
                Nat Genet
                Nature genetics
                Springer Science and Business Media LLC
                1546-1718
                1061-4036
                Feb 2014
                : 46
                : 2
                Affiliations
                [1 ] Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
                [2 ] School of Medicine, University of Queensland, Brisbane, Australia.
                [3 ] Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Australia.
                [4 ] Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA.
                [5 ] Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan.
                [6 ] Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, Safat, Kuwait.
                [7 ] Department of Lab Medicine and Pathobiology, University of Toronto, Canada.
                [8 ] Danish HNPCC Registry, Copenhagen, Denmark.
                [9 ] Surgical Gastroenterology Department, Aalborg University Hospital, Aalborg, Denmark.
                [10 ] Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, Barcelona, Spain.
                [11 ] Center of Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
                [12 ] Molecular Genetics Lab, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Melbourne, Australia.
                [13 ] INSERM UMR S910, Department of Medical Genetics and Functional Genomics, Marseille, France.
                [14 ] Department of Cancer Genetics, Mater Private Hospital, Dublin, Ireland.
                [15 ] Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland.
                [16 ] Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
                [17 ] Inserm U1079, Faculty of Medicine, Institute for Biomedical Research, University of Rouen, France.
                [18 ] Department of Dermatology, University of Utah Medical School, Salt Lake City, UT, USA.
                [19 ] Huntsman Cancer Institute, Salt Lake City, UT, USA.
                [20 ] Center for Molecular Medicine, UConn Health Center, Farmington, CT, USA.
                [21 ] Neag Comprehensive Cancer Center, UConn Health Center, Farmington, CT, USA.
                [22 ] MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
                [23 ] Klinikum der Universität München, Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Munich, Germany.
                [24 ] School of Medicine, University of Western Sydney, Sydney, Australia.
                [25 ] The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.
                [26 ] St Vincent's Clinical School, University of NSW, Sydney, Australia.
                [27 ] Department of Molecular Medicine and Surgery, Karolinska Institutet, Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
                [28 ] Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
                [29 ] Inserm U1079, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
                [30 ] Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
                [31 ] Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland.
                [32 ] Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland.
                [33 ] Center for Genetic and Genomic Medicine, The First Affiliated Hospital of Zhejiang University School of Medicine, James Watson Institute of Genomic Sciences, Beijing Genome Institute, China.
                [34 ] University of Rochester Medical Center, NY, USA.
                [35 ] MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
                [36 ] Center for Healthy Aging, University of Copenhagen, Denmark.
                [37 ] Institute of Human Genetics, University of Düsseldorf, Germany.
                [38 ] Discipline of Medical Genetics, Faculty of Health, University of Newcastle, The Hunter Medical Research Institute, NSW, Australia.
                [39 ] The Division of Molecular Medicine, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia.
                [40 ] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
                [41 ] State University of New York at Downstate, Brooklyn, NY, USA.
                [42 ] Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
                [43 ] Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Italy.
                [44 ] Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy.
                Article
                NIHMS556130
                10.1038/ng.2854
                4294709
                24362816
                1babd710-58c6-4c0c-abd5-a25ac6d0d4bd
                History

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