What is VarSome Clinical PGx?

Pharmacogenomics (PGx) report generation is a new functionality that is introduced in VarSome Clinical version 11.7. PGx reporting can be enabled at the request of your group administrator, it is not available by default.

The PGx report will be available for Whole Genome Sequencing (WGS) analyses that were analyzed against the hg38 reference genome, and it will run as an additional analysis step. 

VarSome Clinical's PGx feature will use the current output of analyses, namely variant calling files (VCF) files, to generate pharmacogenomics reports. PGx report generation in VarSome Clinical is based on PharmCAT, a dedicated software tool PGx report generation. The tool extracts all Clinical Pharmacogenetics Implementation Consortium (CPICⓇ) guideline gene variants from a genetic dataset, represented as a VCF file, interprets the variant alleles, and generates a report. The version  integrated into VarSome Clinical 11.7 is pharmCAT 2.2.2 (released 01-02-2023).

PharmCAT will attempt to match a total of 18 genes (DPYD, CACNA1S, UGT1A1, ABCG2, TPMT, CYP3A5, CYP3A4, CFTR, CYP2C19, CYP2C9, SLCO1B1, NUDT15, VKORC1, CYP4F2, RYR1, IFNL3, CYP2B6, G6PD) with alleles and drug dosage information for 123 drugs. A complete list of the drugs is given here. A total of 774 variant locations within those genes are considered in matching star alleles.

How to Run

The PGx report will be generated for the following analyses:

  • Whole Genome Sequence analyses 
  • Reference genome is hg38. 

The option to run the analysis automatically will be activated when the criteria are met ( WGS samples and hg38 only). 

The VarSome Clinical PGx report

The user will be able to download the report from the download options:

The report comprises 4 sections: 

  • Genotype Summary: This section has a summarized table of the matched genotypes and the following associated clinical annotations: Drug, Gene, Allele Functionality and Phenotype
  • Prescribing Recommendations: This section includes a list of recommendations per associated drug, along with bibliographical reference material
  • Allele Matching Details: Detailed information about how data in the sample VCF matches up with haplotype definitions
  • Disclaimers: PharmCAT disclaimer as stated in their website.

Warning - Note to the User

Typically in WGS samples, a large fraction of the PGX relevant positions that are considered by pharmCAT are absent from the input vcf. If those missing positions are assumed to be “no-call”, the resulting PGx report results in the output of multiple possible genotypes, and hence less specific treatment recommendations.

In VarSome Clinical 11.7, we assume that all missing PGx relevant positions are homozygous reference. However, this may not reflect reality, because such positions may in fact be unreadable or uncallable. Running PharmCAT with positions as missing vs reference can lead to different results.