However, they are deliberately broad in scope, with the intention that individual rules would be interpreted and adapted for specific diseases within the overall framework. The ACMG/AMP guidelines outline how different lines of evidence should be assessed when interpreting a variant, and the strength of evidence required for a pathogenic (or likely pathogenic) classification. A critical objective of the guidelines is to limit false-positive results in clinical genetic testing in order to avoid genetic misdiagnosis or false reassurance through predictive testing of a variant that is not causal.
These were in part prompted by the plethora of erroneous variant-disease associations in the research literature and the increasing realisation that individually rare variants are collectively common for many genes, as highlighted by population datasets such as the Exome Aggregation Consortium (ExAC). In an effort to standardise variant assessment in clinical settings, guidelines from the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) were produced in 2015 and have now been widely adopted. Advances in sequencing technology have dramatically expanded the scope for genetic testing in rare Mendelian diseases, but have exposed variant interpretation as a key limiting factor for clinical application.
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