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Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium
- Source :
- The American Journal of Human Genetics. 99(1)
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Biomedical Research
Evidence-based practice
Concordance
MEDLINE
Exploratory research
Guidelines as Topic
Genomics
Computational biology
030105 genetics & heredity
Bioinformatics
Article
03 medical and health sciences
Genetics
Humans
Medicine
Exome
Genetics(clinical)
Genetic Testing
Genetics (clinical)
Genetic testing
Incidental Findings
medicine.diagnostic_test
Genome, Human
Molecular pathology
business.industry
Interpretation (philosophy)
Genetic Variation
High-Throughput Nucleotide Sequencing
Correction
Sequence Analysis, DNA
United States
Human genetics
3. Good health
030104 developmental biology
Data Interpretation, Statistical
Evidence-Based Practice
Mutation
Medical genetics
Laboratories
business
Software
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 99
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....1127342bb8a73611544cd4f3b616ba57
- Full Text :
- https://doi.org/10.1016/j.ajhg.2016.06.001