A New Framework for the Use of Variant Interpretation Tools in Clinical Practice
Year: 2023
Type: conference-paper
Abstract: Current ACMG/AMP guidelines for the use of sequence variants for genetic diagnosis \nand treatment permit the use of in silico predictors as Supporting evidence (PP3 and \nBP4 criteria). These criteria, however, lack quantitative support and leave clinicians and \nscientists without standards for applying these criteria, leading to large interpretation \nvariability. To address this challenge, our team built upon previous work and introduced \na novel criterion that can be used to calibrate any computational model or any other \ncontinuous-scale evidence on any variant type. We used it to estimate score intervals \ncorresponding to the four strengths of evidence for pathogenicity and benignity for \nfourteen missense variant interpretation tools on a carefully assembled data sets of \nknown pathogenic and benign variants. We found that most tools achieved the Supporting \nevidence level for both pathogenic and benign classification using newly established datadriven \nthresholds. Importantly, at appropriate score thresholds, several in silico methods \ncan also provide Moderate and Strong evidence levels for a limited number of variants. \nBased on these findings, we provided recommendations for quantitative revisions of the \nPP3 and BP4 criteria within ACMG/AMP guidelines and the future assessment of in silico \nmethods for clinical interpretation.
Author: Radivojac, Predrag
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7011755119