Clinically relevant scores

[biolancer]

Description of feature

The DNPM KDS draft includes a set of clinically relevant scores which can be calculated and derived from data generated during alignment and variant calling. As a long-term feature, these scores could be calculated in our pipeline based on consented or established methods generating the required output for the DNPM or clinical interpretation.

Scores requiring alignment data:

• In-silico tumor purity
• Tumor Mutational Burden (TMB; could also be roughly assessed using ROI and VCF data, but more sophisticated approaches should be preferred)
• Micro Satellite Instability Score (MSI)
• Homologous Repair Deficiency Score (HRD)

Score requiring variant call data:

• BRCAness (defined as the percentual exposure to SBS3 + confidence interval per sample)

Future assessment of these scores should be considered based on prevalent benchmarking of suitable methods.

[biolancer]

I would have a proposal for a TMB calculation module. It assumes tumor-only sequencing and requires only a VCF and BED file as input and works following this procedure:

• The annotated VCF will be checked for mutations with an population specific allele count above 10 in the gnomAD database.
• Strict filter routines: >= 5 % AF, at least 50X Coverage, must be in the targeted assay area
• Afterwards, it bins mutations with comparable allele frequency across each genome and generates a ratio of filtered to unfiltered mutations for each bin.
• If the ratio for a bin favors filtering and has at least 5 mutations marked for filtering, other eligible mutations in said bin will also be filtered.
• In a last step, mutations above 90 % AF will also be filtered.

The final TMB score would then be Eligible Variants / Effective panel size (in Mutations per MBp). The whole procedure follows the current implementation of the TSO500 RunManager app for TMB calculation and sounds reasonable to me.