Industry Leaders Recommend Standardized Interpretation and Reporting of Somatic Sequence Variants

Acommon refrain within the diagnostics industry is a need for standardization. Rapidly developing technology and testing methods, the call for interoperability, and the vast amount of data and information producible via molecular testing makes this even more important. The capabilities of next generation sequencing have provided both opportunities and challenges as clinical laboratories interpret and report results of cancer-related sequencing tests.

Now, the Association for Molecular Pathology (AMP) has released guidelines developed by an industry working group that recommend standard classification, annotation, interpretation and reporting for somatic sequence variants in cancer. The AMP was joined in this effort by the American College of Medical Genetics and Genomics (ACMG), American Society of Clinical Oncology (ASCO), and College of American Pathologists (CAP).

"Cancer genomics is a rapidly evolving field so the clinical significance of any variant in therapy, diagnosis, or prognosis should be reevaluated on an ongoing basis by all of the key stakeholders," said one working group member, Marina N. Nikiforova, MD, Professor of Pathology at University of Pittsburgh Medical Center, in a statement announcing the release of the guidelines. Nikiforova is also the 2016 AMP Clinical Practice Committee Chair and adds, "These new recommendations resulted from the successful ACMG, AMP and CAP efforts on germline variant interpretation and were additionally informed by the diverse perspectives expressed at the ASCO, AMP and CAP Genomic Roundtable stakeholder discussions." The Guidelines will be published in the January 2017 issue of The Journal of Molecular Diagnostics but were released online by AMP in December.

To gain insight into the real world operations of varying laboratories, the working group solicited surveys from AMP members. The surveys focused on technical issues and reporting issues. They received 67 responses on technical issues and 44 for reporting issues. Survey responses revealed variation among NGS techniques used and the annotation and reporting of variants.

The U.S. Food and Drug Administration has similarly led industry-wide discussion of standards for NGS interpretation and reporting. Recognizing the vast amount of information that can be yielded from NGS, the difficulty in interpreting results of NGS testing and lack of evidence in some cases linking genetic variants to specific diseases a recent FDA workshop discussed how best to make use of the results of NGS testing—based on patient and provider preferences. The goal, the notice of the workshop announced, is "to learn, when results are generated in a CLIA-compliant laboratory, which results are of importance to patients and providers, how these results should be returned and how much and what types of evidence supporting interpretation of those results is necessary."

Tiered classification system
The Guidelines share several recommendations for laboratories involved in such NGS variant testing for cancer. To categorize variants, the guidelines recommend using a tiered system that categorizes somatic variants according to their impact on clinical care—using "currently available evidence."

• Tier I would be variants with strong clinical significance based on evidence regarding FDA approved therapy and "well-powered studies with consensus from experts in the field."

• Tier II covers variants of potential clinical significance based on evidence from FDA approved treatments but for different tumor types or investigational therapies, small published studies having some consensus, and preclinical trials or case reports without consensus.

• Tier III includes variants of unknown clinical significance when there is no "convincing published evidence of cancer association" and the variant isn't "observed at a significant allele frequency in the general or specific subpopulation databases, or pan-cancer or tumor-specific variant databases."

• Tier IV is for benign or likely benign variants when there is a lack of published evidence of cancer association and the variant is "observed at significant allele frequency in the general or specific subpopulation databases."

For further discussion of the guidelines see the December 2016 issue of Diagnostic Testing & Emerging Technologies.