Since 2017, the molecular pathology community has relied on the AMP/ASCO/CAP guidelines for somatic variant interpretation for standardizing how genetic alterations are classified and reported in cancer. Now, in 2025, proposed updates to these guidelines address a critical gap in the original framework – one that has led to inconsistent practices across laboratories.
The Original Framework
The 2017 guidelines established a tiered system based on therapeutic, prognostic, or diagnostic significance:
- Tier IA: Strong Clinical Significance (FDA-approved therapies or professional guidelines)
- Tier IB: Strong Clinical Significance (Consensus-driven)
- Tier IIC: Potential Clinical Significance (Investigational therapies, small published studies, approved therapy for different tumor type)
- Tier IID: Potential Clinical Significance (Case study level evidence)
- Tier III: Unknown Clinical Significance (VUS)
- Tier IV: Benign or Likely Benign
The Hidden Challenge
While this framework was valuable for moving toward standardization, it created an unexpected dilemma in practice: how should we classify variants that are oncogenic/likely oncogenic but lack clear therapeutic, prognostic, or diagnostic implications?
This gap has led to two divergent approaches in the field:
The first camp takes a stricter interpretive approach, classifying oncogenic variants without clear clinical impact as Tier 3 (VUS). While this technically adheres to the guidelines, it creates a confusing situation where Tier 3 contains two fundamentally different types of variants: those that are known to be oncogenic but lack clinical significance, and those whose very role in cancer biology remains uncertain.
The second camp, aiming to avoid this confusion, strives to classify all oncogenic variants as at least Tier 2. However, this often requires stretching the evidence for clinical significance beyond reasonable limits, potentially undermining the rigor of the classification system.
The 2025 Update: A Clear Path Forward
A proposed update to the guideline directly addresses this challenge by introducing Tier IIE / Tier 2E:
“…a fifth evidence classification level… (Level E) classified as oncogenic or likely oncogenic based on oncogenicity assessment but lacking clear evidence of clinical diagnostic, prognostic, or therapeutic significance in the tumor tested based on the currently available clinical evidence.”
This addition to the existing tier system provides a logical home for these variants within Tier II, making it clear that while these variants are important drivers of cancer, they currently lack direct clinical impact. This modification eliminates the need for laboratories to choose between two suboptimal options.
This update represents a significant improvement in several ways:
1. It acknowledges the reality that not all cancer-driving mutations have immediate clinical implications
2. It maintains the integrity of the VUS category for truly uncertain variants
3. It eliminates the pressure to overstate clinical evidence just to avoid classifying oncogenic variants as VUS
