Germline variants

To explore germline variants that might play a role in tumor analysis, it is recommended to run an additional analysis, the DRAGEN Germline pipeline, on the normal sample. The highest performance for the detection of both somatic and germline variants is achieved by implementing the Tumor/Normal (T/N) Somatic Variant Calling workflow and additionally the dedicated Germline pipeline on the Normal sample.

How It Works

In somatic T/N analysis, DRAGEN uses a subtraction model for small variants (SNVs and indels). The matched normal provides a more reliable indicator of somatic variants than comparisons with public databases. Because the T/N model identifies variants where there are no (or very few) alternate-supporting reads in the normal sample, germline variants (present in both the tumor and normal sampeles) are intentionally suppressed from the somatic VCF output.

To recover germline variants, a dedicated germline pipeline should be run on the normal sample. This caller uses a different statistical model optimized for diploid genotyping, evaluating evidence for heterozygous (0/1) and homozygous alternate (1/1) calls at expected allele fractions of ~50% and ~100%, respectively. It also produces calibrated quality metrics (GQ, PL) expected by downstream clinical interpretation workflows.

Running both the somatic pipeline on the tumor-normal pair and the germline pipeline on the normal sample ensures that each variant type is called by the model best suited to detect it. The resulting somatic and germline VCFs are output from separate analyses and can be used independently or merged as needed for reporting. DRAGEN software development is ongoing to streamline these two analyses.