Comparison of next-generation sequencing platforms. The optimal sequencing platform to use for clinical testing is dependent on several variables, include the cost, breadth of sequencing coverage (ie, the number of mutations that can be detected), and the typical sequencing depth obtained (ie, the sensitivity of variant detection). Although WGS provides the greatest breadth, the standard depth of coverage (30-45×) limits detection of variants to those with a VAF typically >10%. WES only provides coverage of coding bases in the genome, but the greater sequencing depth (typically 75-150×) allows for detection of mutations with VAFs as low as 5%. Gene panel sequencing is limited to the most commonly mutated genes but can detect mutations at lower VAFs. A typical 100-gene panel with 1000× coverage depth can detect mutations with VAFs as low as 2%, at a reasonable cost. Finally, error-corrected sequencing provides extremely high-depth coverage (10 000×) along with error correction via unique molecular indexes, together allowing for detection of VAFs < 1%. Error-corrected sequencing and gene panel sequencing approaches offer a large degree of flexibility, because they can be used to validate mutations (ie, those detected by WGS), track mutations, or discover mutations. In addition, these methods are often used without paired normal DNA to detect variants. However, germline DNA is necessary to definitively identify somatic mutations (+/−). Adapted from Jacoby et al.⁹⁰