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      Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

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          Abstract

          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence ( e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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          Most cited references 38

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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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            Prospects for whole-genome linkage disequilibrium mapping of common disease genes.

             L Kruglyak (1999)
            Recently, attention has focused on the use of whole-genome linkage disequilibrium (LD) studies to map common disease genes. Such studies would employ a dense map of single nucleotide polymorphisms (SNPs) to detect association between a marker and disease. Construction of SNP maps is currently underway. An essential issue yet to be settled is the required marker density of such maps. Here, I use population simulations to estimate the extent of LD surrounding common gene variants in the general human population as well as in isolated populations. Two main conclusions emerge from these investigations. First, a useful level of LD is unlikely to extend beyond an average distance of roughly 3 kb in the general population, which implies that approximately 500,000 SNPs will be required for whole-genome studies. Second, the extent of LD is similar in isolated populations unless the founding bottleneck is very narrow or the frequency of the variant is low (<5%).
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              A "Copernican" reassessment of the human mitochondrial DNA tree from its root.

              Mutational events along the human mtDNA phylogeny are traditionally identified relative to the revised Cambridge Reference Sequence, a contemporary European sequence published in 1981. This historical choice is a continuous source of inconsistencies, misinterpretations, and errors in medical, forensic, and population genetic studies. Here, after having refined the human mtDNA phylogeny to an unprecedented level by adding information from 8,216 modern mitogenomes, we propose switching the reference to a Reconstructed Sapiens Reference Sequence, which was identified by considering all available mitogenomes from Homo neanderthalensis. This "Copernican" reassessment of the human mtDNA tree from its deepest root should resolve previous problems and will have a substantial practical and educational influence on the scientific and public perception of human evolution by clarifying the core principles of common ancestry for extant descendants. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Chair, ACMG
                Role: CAP
                Role: ACMG
                Role: ACMG
                Role: ACMG
                Role: AMP
                Role: ACMG
                Role: ACMG
                Role: AMP
                Role: ACMG
                Role: CAP
                Role: Co-Chair, ACMG On behalf of : On behalf of the ACMG Laboratory Quality Assurance Committee
                Journal
                9815831
                22061
                Genet Med
                Genet. Med.
                Genetics in medicine : official journal of the American College of Medical Genetics
                1098-3600
                1530-0366
                11 August 2015
                05 March 2015
                May 2015
                01 November 2015
                : 17
                : 5
                : 405-424
                Affiliations
                Knight Diagnostic Laboratories; Department of Molecular and Medical Genetics; Oregon Health & Science University, Portland, OR, USA
                College of American Pathologists, Chicago, IL, USA
                GeneDx, Gaithersburg, MD, USA
                Section of Genetics, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, USA
                Department of Human Genetics, Clinical Molecular Genetics Laboratory, The University of Chicago, Chicago, USA
                Nationwide Children's Hospital, Cytogenetics/Molecular Genetics Laboratory; Ohio State University College of Medicine, Departments of Pathology and Pediatrics, Columbus, OH, USA
                Departments of Pathology & Laboratory Medicine, Pediatrics, and Human Genetics, UCLA School of Medicine, Los Angeles, CA, USA
                Emory Genetics Laboratory, Department of Human Genetics, Emory University, Atlanta, Georgia, USA
                Department of Pathology, ARUP Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, Utah, USA
                Molecular Genetics Laboratory, Children’s Hospital Colorado, Department of Pediatrics, University of Colorado Anschutz Medical School, Denver, CO, USA
                Department of Pathology, ARUP Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, Utah, USA
                Partners Laboratory for Molecular Medicine and Department of Pathology, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
                Author notes

                Nazneen Aziz. Current address: Phoenix Children’s Hospital

                Article
                NIHMS697486
                10.1038/gim.2015.30
                4544753
                25741868
                Categories
                Article

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