Abstract
Clinical genetics laboratories have recently adopted guidelines for the interpretation of sequence variants set by the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP). The use of in silico algorithms to predict whether amino acid substitutions result in human disease is inconsistent across clinical laboratories. The clinical genetics community must carefully consider how in silico predictions can be incorporated into variant interpretation in clinical practice.Please see related Research article: https://doi.org/10.1186/s13059-017-1353-5
Highlights
Clinical genetics laboratories have recently adopted guidelines for the interpretation of sequence variants set by the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP)
Standardization of variant interpretation Professional standards and guidelines for clinical interpretation of sequence variants by the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) [1] are widely adopted into clinical practice. These guidelines provide a framework for laboratories to evaluate the disease causality of sequence variants in a consistent manner and recommend the classification of these variants into five categories: pathogenic, likely pathogenic, uncertain, likely benign, or benign based on the strength of evidence, which is classified
A critical tenet of these standards is that variant classification must be dependent upon scientific evidence and weighted according to the type of evidence available, which includes functional studies, segregation studies, comparison of the variant frequency in patients versus the general population, clinical correlation between gene and clinical features of the patient, inferences based on knowledge of the gene or protein structure, in silico predictions, and other evidence detailed in the ACMG/ AMP guidelines [1]
Summary
Clinical genetics laboratories have recently adopted guidelines for the interpretation of sequence variants set by the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP). These guidelines provide a framework for laboratories to evaluate the disease causality of sequence variants in a consistent manner and recommend the classification of these variants into five categories: pathogenic, likely pathogenic, uncertain (variant of uncertain significance; VUS), likely benign, or benign based on the strength of evidence, which is classified
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