Inter-lab concordance of variant classifications establishes clinical validity of expanded carrier screening

Abstract

Expanded carrier screening (ECS) panels that use next-generation sequencing aim to identify pathogenic variants in coding and clinically relevant non-coding regions of hundreds of genes, each associated with a serious recessive condition. ECS has established analytical validity and clinical utility, meaning that variants are accurately identified and pathogenic variants tend to alter patients' clinical management, respectively. However, the clinical validity of ECS, that is, correct discernment of whether an identified variant is indeed pathogenic, has only been shown for single conditions, not for panels. Here, we evaluate the clinical validity of a >170-condition ECS panel by assessing concordance between >12 000 variant interpretations classified with guideline-based criteria to their corresponding per-variant combined classifications in ClinVar. We observe 99% concordance at the level of unique variants. A more clinically relevant frequency-weighted analysis reveals that fewer than 1 in 500 patients are expected to receive a report with a variant that has a discordant classification. Importantly, gene-level concordance is not diminished for rare ECS conditions, suggesting that large panels do not balloon the panel-wide false-positive rate. Finally, because ECS is intended to serve all reproductive-age couples, we show that classification of novel variants is feasible and scales predictably for a large population.