Interpretation of Variants in Clinical Genomics

Abstract

Abstract Many health conditions are genetic in origin, and it is often necessary to identify the causative DNA variant(s) in the patient in order to confirm a potential genetic diagnosis, so that optimal management and/or treatment can be implemented. This process can be complicated by the massive amount of variation present in all our genomes, so that distinguishing pathogenic variants from benign ones can be challenging. In order to provide consistency and improved validity of interpretations from different diagnostic laboratories across the world, professional guidelines have recently been published which specify how various types of evidence from scientific literature, databases, functional studies and in silico analysis should be combined to generate a classification for a variant. Ongoing work seeks to improve these guidelines, including the generation of versions specific for particular conditions and specific guidelines for classification of copy number variants and somatic variants. Key Concepts Analysis of patient DNA to identify pathogenic variants is often a critical step in confirming a genetic diagnosis. Most of the variants found in any human genome are benign, so clinical scientists need to be able to identify which are (likely) pathogenic. Other reports of a variant, in scientific literature or databases, and/or reports from functional assays can help to classify variants as (likely) benign or (likely) pathogenic. Computer software can be used to conduct in silico analysis to predict potential pathogenicity of a variant. Professional guidelines have been generated for combining different types of evidence during variant interpretation, and these are used internationally, to ensure consistent outcomes in variant interpretation, both in general use and for specific genetic conditions. Despite careful evaluation according to the guidelines, many variants identified in patient DNA remain as variants of uncertain significance (VUS) due to insufficient or contradictory evidence.