Genotype and Phenotype Concordance for Pharmacogenetic Tests Through Proficiency Survey Testing

Abstract

Context.-As pharmacogenetic testing is incorporated into routine care, it is essential for laboratories to provide accurate and consistent results. Certified laboratories must successfully complete proficiency testing.Objectives.-To understand and examine trends in participation and performance of laboratories participating in the College of American Pathologists pharmacogenetic proficiency testing surveys.Design.-Results from College of American Pathologists pharmacogenetic proficiency testing challenges from 2012 through 2017 were reviewed for concordance with expected genotype and phenotype for each sample (intended responses).Results.-Laboratories correctly reported results for 96.7% to 100% of samples with no variants. Excluding CYP2D6, laboratories correctly detected and reported variant alleles for each gene (93.7%-99.2% correct).CYP2D6 showed lower concordance, with 83.1% of laboratories reporting the intended genotype across all samples; however, in many cases, the laboratories that did not report a variant allele did not test for that allele. Among laboratories reporting the intended genotype, most successfully reported the intended phenotype (85.9%-99.0%).Conclusions.-Although laboratories are generally performing well, there is room for additional improvement, particularly for challenging genes, such as CYP2D6. Efforts in the field of pharmacogenomics to recommend alleles that should be included in clinical tests, identify reference materials, and standardize translation from genotype to phenotype may address some of the remaining variability in results.(Arch Pathol Lab Med.

PharmVar Tutorial on CYP2D6 Structural Variation Testing and Recommendations on Reporting

“…According to recent proficiency testing data, the majority of laboratories can detect the CYP2D6*5 deletion allele, whereas many laboratories either do not detect duplications or only utilize one position. 59,101,102 These recommendations were published in 2021, and it may take time for laboratories to update their processes and to adopt them. Information on available laboratory tests, including which alleles are tested can be found in the Genetic Testing Registry.…”

“…Laboratories must demonstrate accurate and consistent CYP2D6 testing results before incorporating the test into clinical care. 101 This process is facilitated, in part, by access to publicly available data and reference materials maintained by the Centers for Disease Control and Prevention's Genetic Testing Reference Materials Program (GeT-RM) and Coriell Cell Repositories, respectively. To date, 179 Coriell samples have undergone extensive CYP2D6 characterization, and some have been found to carry rare or difficult-to-analyze CYP2D6 alleles, including SVs/ CNVs.…”

Recommendations for Clinical CYP2D6 Genotyping Allele Selection

“…While most CYP2D6 hybrid alleles are generally considered to be nonfunctional, they can complicate CYP2D6 copy number analysis, particularly if the test only queries CYP2D6 gene copy number at one position. 27,73,74 For example, if a laboratory's copy number assay is designed to query exon 1 of CYP2D6 and a CYP2D6-CYP2D7 hybrid gene is present, the laboratory may mistake the hybrid gene for a 'full' copy of the CYP2D6 gene (Table 4). Using only one location within CYP2D6 for copy number can satisfy the Tier 1 recommendation to identify the CYP2D6*5 deletion or gene duplication, however, it is recommended to use at least two, if not multiple locations, to detect hybrid alleles.…”