Standardization of Somatic Variant Classifications in Solid and Haematological Tumours by a Two-Level Approach of Biological and Clinical Classes: An Initiative of the Belgian ComPerMed Expert Panel

Abstract

In most diagnostic laboratories, targeted next-generation sequencing (NGS) is currently the default assay for the detection of somatic variants in solid as well as haematological tumours. Independent of the method, the final outcome is a list of variants that differ from the human genome reference sequence of which some may relate to the establishment of the tumour in the patient. A critical point towards a uniform patient management is the assignment of the biological contribution of each variant to the malignancy and its subsequent clinical impact in a specific malignancy. These so-called biological and clinical classifications of somatic variants are currently not standardized and are vastly dependent on the subjective analysis of each laboratory. This subjectivity can thus result in a different classification and subsequent clinical interpretation of the same variant. Therefore, the ComPerMed panel of Belgian experts in cancer diagnostics set up a working group with the goal to harmonize the biological classification and clinical interpretation of somatic variants detected by NGS. This effort resulted in the establishment of a uniform, two-level classification workflow system that should enable high consistency in diagnosis, prognosis, treatment and follow-up of cancer patients. Variants are first classified into a tumour-independent biological five class system and subsequently in a four tier ACMG clinical classification. Here, we describe the ComPerMed workflow in detail including examples for each step of the pipeline. Moreover, this workflow can be implemented in variant classification software tools enabling automatic reporting of NGS data, independent of panel, method or analysis software.

FDG positron emission tomography imaging and ctDNA detection as an early dynamic biomarker of everolimus efficacy in advanced luminal breast cancer

“…Plasma ctDNA was sequenced to identify hotspot mutations in 40 cancer-specific genes (Supplementary Table 1 ) with coverage of 15000× using the commercially available next-generation sequencing panel. For variants classification, we followed the Compermed method 22 .…”

Evaluation of a Targeted Next-Generation Sequencing Panel for the Non-Invasive Detection of Variants in Circulating DNA of Colorectal Cancer

“…Importantly, many of the variants detected were frameshift, inframe, missense, and stop gain variants. These types of variants are associated with the capability of producing clinically relevant effects in genes driving cancer progression [ 26 ]. Therefore, detection of these variants in our work supports the possibility of using the TST170 panel, not only in tissue samples, but also in cfDNA in a research or clinical setting.…”

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial

“…A validated homebrew bioinformatics pipeline provided variants that were biologically and clinically classified according to the Belgian ComPerMed (v1) guidelines. 38 Total RNA was isolated from FFPE-pretreated tumor biopsies. Initially, tumor samples from 21 patients were selected; total RNA extraction was sufficient for 18 tumor samples.…”