A framework for the evaluation and reporting of incidental findings in clinical genomic testing

Abstract

Currently, there are no widely accepted recommendations in the genomics field guiding the return of incidental findings (IFs), defined here as unexpected results that are unrelated to the indication for testing. Consequently, reporting policies for IFs among laboratories offering genomic testing are variable and may lack transparency. Herein we describe a framework developed to guide the evaluation and return of IFs encountered in probands undergoing clinical genome sequencing (cGS). The framework prioritizes clinical significance and actionability of IFs and follows a stepwise approach with stopping points at which IFs may be recommended for return or not. Over 18 months, implementation of the framework in a clinical laboratory facilitated the return of actionable IFs in 37 of 720 (5.1%) individuals referred for cGS, which is reduced to 3.1% if glucose-6-phosphate dehydrogenase (G6PD) deficiency is excluded. This framework can serve as a model to standardize reporting of IFs identified during genomic testing.

Fig. 1. Evaluating clinical significance of potential IFs by variant type.

These flowcharts display the steps used to establish the clinical significance of IFs by variant type. Only variants meeting clinical significance criteria proceed to part II of the framework, which assesses actionability (Fig. 2). A, C Single gene IFs (single nucleotide variants, small insertions and deletions and CNVs impacting one gene) in nuclear and mitochondrial genes must (1) occur in a zygotic state or at a level of heteroplasmy expected to produce a phenotype, (2) occur in a gene with a gene–disease relationship classified as strong or definitive according to the ClinGen gene–disease validity framework [18] and (3) have a variant classification of likely pathogenic or pathogenic (P/LP) according to ACMG/AMP/ClinGen criteria [22, 23, 25]. B CNVs impacting multiple genes must occur in a zygotic state expected to produce a phenotype and must be classified as P/LP according to ACMG/ClinGen criteria [24]. AR autosomal recessive; AD autosomal dominant; CNV copy number variant; P pathogenic; LP likely pathogenic; VUS variant of uncertain significance; VRF variant read fraction. *Further evaluated on a case-by case basis using bioinformatic tools and/or clinical judgment.

Fig. 2. Assessing the actionability of clinically significant IFs.

This flowchart displays the steps used to evaluate the actionability of IFs which meet the clinical significance criteria outlined in part I of the framework (Fig. 1). Only IFs meeting both clinical significance and actionability criteria are recommended for return on the clinical reports of probands undergoing cGS.