CSER sites explore application of 2015 ACMG-AMP Variant Interpretation Guidelines

University of Washington researchers (from left to right) Laura Amendola, Gail Jarvik, and Michael Dorschner contributed to the CSER "Variant Bake-off". In particular, Laura and Gail are lead authors for the paper.

The CSER consortium pilot evaluating the 2015 ACMG-AMP variant interpretation guidelines was published online this week in the American Journal of Human Genetics. For this project, 9 CLIA genome/exome labs used both the ACMG-AMP guidelines and their local frameworks to classify the pathogenicity of 99 variants. Differences in variant interpretation within and between labs were identified demonstrating the difficulty and subjectivity of variant classification even when using a common set of rules. However, the ACMG/AMP guideline facilitated discussions of evidence criteria enabling resolution of most differences in variant interpretation as well as identifying aspects of the ACMG/AMP criteria that could be better clarified or quantified for more accurate and objective use. The minority of unresolvable differences in variant interpretation underscore that variant interpretation is still subject to professional judgment (even when using the same rules) and therefore complete consensus may not occur for all variants.

This paper is can be found online at AJHG here.