2. Oncogenicity and AMP Tiers

VSClinical serves as the ACMG and AMP guideline interpretation hub and allows for creating more intuitive workflows and higher consistency in results. In the case of the ACMG Guidelines, VSClinical provides a workflow that integrates the exact criteria and classification rules to follow the guidelines like shown below.

pathogenicity scoring

Figure 2-1: Pathogenic classification recommendations.

The Golden Helix Oncogenicity Score was developed to provide a criteria-based scoring system similar to the ACMG guidelines but with the numeric pathogenicity scale introduced by Invitae’s Sherloc scoring system. Many of the scoring criteria are similar if not identical to those used by the ACMG guidelines, while others are specialized to match somatic annotations and clinical evidence. For example, missense variants are checked against the cancer hotspot annotation as well as active binding sites as these are often present for activating missense mutations. The criteria and strengths were developed in consultation with the GA4GH Variant Interpretation in Cancer Consortium (VICC).

Similar to the Pathogenicity Score produced by the ACMG Guidelines, the Oncogenicity Score allows the user to get a quick snapshot of how much evidence is pushing the variant in a direction that warrants more careful review or whether it can be safely ignored as Benign. In fact, the Benign and Likely Benign classifications utilize the exact same criteria, rules and thresholds as the ACMG scoring system. Because it is based on numeric criteria, the summation of all scored criteria place the variant on a scale from Benign to Oncogenic.

oncogenicity scoring

Figure 2-2: Oncogenicity scoring recommendations.

After a variant is suspected to be Oncogenic, the next level of evaluation is to consider the variant as a Biomarker for the current patient’s tumor type. This requires a review of many sources of clinical evidence that may contain links between this biomarker and targeted therapies as well as potential diagnostic and prognostic implications.

The AMP Guidelines provide a rubric to grade the summation of this clinical evidence and categorize these into “tiers”. To reach Tier 1, a variant of strong clinical significance would require Level A and B evidence i.e. known FDA approved therapies or well powered studies with expert consensus respectively. While Tier II variants of potential significance require level C and D evidence which is FDA approved treatments for different tumor types, investigational therapies, multiple published studies with consensus, or preclinical trials with case reports. Tier III variants of unknown clinical significance will have little or no presence in general frequency, nor cancer specific databases and no publications with cancer association. Lastly, Tier IV variants are benign or likely benign due to high allele frequency in population databases and have no published evidence for association to cancer.

oncogenicity scoring

Figure 2-3: FDA Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer (2017).

The capture of all this relevant evidence to determine the tier is a large undertaking, but VSClinical creates the ability to not only automate the classification process but also automate the presentation of all relevant content in a final report.