AMP classification guidelines to enhance Rare Disease and Cancer patient care

The ability to identify genomic, transcriptional, proteomic, and epigenetic alterations in tumors has resulted in a better understanding of the progress and impact of different types of patient tumors, and the opportunity to tailor a more precise treatment for each patient. However, unlike interpretation of germline sequence variations, which focuses on the pathogenicity of a variant for a specific disease or disease causality, interpretation of somatic variants is mainly focused on their impact in terms of clinical care. Somatic classification, therefore, is essentially driven by the variant’s clinical impact, which takes into account therapeutic, prognostic, diagnostic, and preventive elements.

AMP Guidelines

A joint effort between The Association for Molecular Pathology (AMP), the American Society of Clinical Oncology (ASCO), and the College of American Pathologists (CAP) has resulted in approved guidelines for standardizing annotation, interpretation, classification, and reporting of somatic sequence variants associated with cancer. Every clinical and experimental evidence related to a variant is labeled by its strength, with a rating from A-D, as shown in the table below:

Categories of Clinical and/or Experimental Evidence

Based on aggregated data of the evidence levels (which include therapeutic, diagnostic and prognostic elements), the variant is then classified into a Tier level system, which in turn reflects their clinical significance, as shown in this chart:

Impact of the Guidelines in Clinical Care

The consortium’s published guidelines provide somatic variants with an enhanced layer of annotation. The published guidelines also offer the following examples of the impact these guidelines could have in a clinical setting.

To illustrate the impact of the guidelines in a clinical setting, the paper brings an example of a melanoma patient that carries the somatic variant BRAF V600E. This specific variant has a Level A therapeutic evidence, since there is an FDA-approved drug for treatments for the BRAF V600E variant in melanoma patients. Based on this level of therapeutic evidence, the BRAF V600E would be classified as a Tier 1 variant.

The guidelines are not only focused on therapeutic evidence though. Another example from the paper is a leukemia patient with a PML-RARA fusion. This fusion is diagnostic for promyelocytic leukemia, and it is also associated with a good prognosis and predicts sensitivity to all trans-retinoic acid or arsenic. This evidence, which would impact the treatment protocol for this specific leukemia patient, is also labeled as Level A but for diagnostic and prognostic purposes, leading to a Tier I classification of the variant as well.

A Layer of Enhanced Annotation to Existing Interpretation

The ACMG germline standards rank variant pathogenicity through multiple criteria; such as population frequency, protein impact, functional data and more. However, the AMP guidelines are mainly rooted in the strength of the therapeutics, prognostic, and diagnostic levels.

For comparison, the variant APC:c.2626C>T found in colorectal carcinoma patients has an ACMG classification of Pathogenic. However, there is a lack of clinically-relevant strong evidence for this variant, and therefore, using the AMP system, it is labeled as Tier II (variant of uncertain significance). This discrepancy in “severity” level emphasizes the difference between the diagnostic view of the variant using ACMG’s methods, and the clinical impact view which is demonstrated in the AMP Classification.

Both systems provide important information, and when used in tandem can give greater insight into patient care. That’s why the Franklin platform for somatic variant analysis presents both automated classification systems in your variant interpretation hub to give a broader understanding of the variant and its potential impact on clinical care.

Moreover, in recent months, several reputable organizations have established new classification guidelines for somatic variants in cancer that aim to offer an oncogenicity-based classification system to complement these AMP guidelines, and will be incorporated into the platform in the coming weeks. Our Franklin Community members will be able to easily utilize and integrate these new and advanced interpretations tools in their patient analysis, giving better predictions surrounding their care. Feel free to read more about these new guidelines, and test the AMP classification system, already available on our Franklin platform.


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