The ClinGen Sequence Variant Interpretation Working Group: Refining Criteria ...Human Variome Project
A key barrier to the efficient clinical utilization of genome sequence data is the lack of a systematic approach for interpreting the pathogenicity of genetic variants, with resultant discordance among laboratories and researchers in classification. The ClinGen (Clinical Genome) Project has been funded by the United States National Institutes of Health with a goal of maximizing the clinical relevance of results from genetic testing. ClinGen has established a Sequence Variant Interpretation (SVI) Working Group to refine and standardize the approach to pathogenicity classification. Recently the American College of Medical Genetics and Genomics (ACMG) published guidelines [1] that emerged from a workgroup that represented the expert opinion of clinical laboratory directors and genetics clinicians. These guidelines were developed to help clinical laboratories that report results from sequencing of single genes, panels, exomes, and genomes. The ClinGen SVI has set short term and long term objectives for advancing the field of pathogenicity interpretation using the ACMG framework as a starting point. There is consensus within the field that correct classification of variants requires integrating multiple lines of evidence, including, clinico-pathologic, epidemiologic, bioinformatics (in silico), and in vitro data. How best to combine them is unclear. The ACMG framework described different categories of evidence and assigned preliminary assessments of what comprises weak or strong evidence favoring a variant’s pathogenicity or neutrality and preliminary rule- based algorithms of how to combine evidence. In the short term, the ClinGen SVI has set up sub-committees to apply more precision in defining criteria for pathogenicity and what comprises strong and weak evidence. In the long term, the ClinGen SVI looks to transition from qualitative descriptions to a quantitative system that can assign an empirically derived probability of pathogenicity for each variant. Preliminary analyses suggest that there will be general rules that apply to all genes, as well as specific approaches for different genetic disorders. Well characterized databases of variants for each genetic disorder will be critical to the process. Funded by the National Human Genome Research Institute through the following three grants: U41 HG006834-01A1, U01 HG007437- 01, U01 HG007436-01, and by the National Cancer Institute through contract HHSN261200800001E. Reference: 1. Richards S, Aziz N, Bale S, et al. 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. Genetics in Medicine2015;17(5):405-424.
The ClinGen Sequence Variant Interpretation Working Group: Refining Criteria ...Human Variome Project
A key barrier to the efficient clinical utilization of genome sequence data is the lack of a systematic approach for interpreting the pathogenicity of genetic variants, with resultant discordance among laboratories and researchers in classification. The ClinGen (Clinical Genome) Project has been funded by the United States National Institutes of Health with a goal of maximizing the clinical relevance of results from genetic testing. ClinGen has established a Sequence Variant Interpretation (SVI) Working Group to refine and standardize the approach to pathogenicity classification. Recently the American College of Medical Genetics and Genomics (ACMG) published guidelines [1] that emerged from a workgroup that represented the expert opinion of clinical laboratory directors and genetics clinicians. These guidelines were developed to help clinical laboratories that report results from sequencing of single genes, panels, exomes, and genomes. The ClinGen SVI has set short term and long term objectives for advancing the field of pathogenicity interpretation using the ACMG framework as a starting point. There is consensus within the field that correct classification of variants requires integrating multiple lines of evidence, including, clinico-pathologic, epidemiologic, bioinformatics (in silico), and in vitro data. How best to combine them is unclear. The ACMG framework described different categories of evidence and assigned preliminary assessments of what comprises weak or strong evidence favoring a variant’s pathogenicity or neutrality and preliminary rule- based algorithms of how to combine evidence. In the short term, the ClinGen SVI has set up sub-committees to apply more precision in defining criteria for pathogenicity and what comprises strong and weak evidence. In the long term, the ClinGen SVI looks to transition from qualitative descriptions to a quantitative system that can assign an empirically derived probability of pathogenicity for each variant. Preliminary analyses suggest that there will be general rules that apply to all genes, as well as specific approaches for different genetic disorders. Well characterized databases of variants for each genetic disorder will be critical to the process. Funded by the National Human Genome Research Institute through the following three grants: U41 HG006834-01A1, U01 HG007437- 01, U01 HG007436-01, and by the National Cancer Institute through contract HHSN261200800001E. Reference: 1. Richards S, Aziz N, Bale S, et al. 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. Genetics in Medicine2015;17(5):405-424.