Specification of frequency criteria for secondary findings genes to improve variant classification concordance.

Abstract

The return of secondary findings is well established in clinical testing and is increasingly used in clinical research testing. Variant classification can be challenging because of the lack of monogenic disease entity (MDE, defined as a gene-phenotype pair)-specific variant classification recommendations. A key criterion for variant classification is disease allele frequency thresholds (DAFTs), which are not established for all MDEs recommended for the return of secondary findings. We calculated DAFTs for secondary finding MDEs considering prevalence, gene contribution, and penetrance. American College of Medical Genetics and Genomics criterion BS1 was set at the calculated DAFT value, with BA1 set at 10 times the calculated DAFT. For genes associated with multiple secondary finding MDEs without clear genotype-phenotype correlation, DAFT values were combined. GnomAD Grpmax filtering allele frequencies for pathogenic/likely pathogenic classified variants were compared with calculated thresholds. We determined BS1 and BA1 values for 58 secondary findings MDEs (47 genes). No pathogenic/likely pathogenic variant Grpmax filtering allele frequency was greater than the relevant MDE-specific BA1. Setting BA1 and BS1 thresholds should improve variant classification consistency and reduce misclassifications. For secondary finding MDEs without current ClinGen Variant Curation Expert Panel specifications, these frequency specifications can be used until full criteria are available.