For the majority of genetic variation, clinical variant pathogenicity cannot be accurately classified based on the variant alone.

It must be done in the context of patient phenotype/diagnosis, ethnicity, and multi-mutational variation. Differences in these factors can cause significant changes in pathogenicity.

In 2017, AMP/ASCO/CAP released a joint consensus recommendation proposing a four-tiered system to categorize somatic sequence variations based on their clinical significance in cancer diagnosis, prognosis, and/or therapeutic. The AMP/CAP/ASCO guidelines underscore the need to focus the interpretation of somatic variants on the impact on clinical care. The guidelines recommend that when one is performing clinical interpretation and classification of sequence variants in cancer, one should:

  • Collect evidence to determine a variant’s clinical significance;
  • Determine its clinical impact for the patient, with respect to diagnosis, prognosis, therapy, and preventative action;
  • Evaluate the strength of the evidence for clinical impact.

 

Collect evidence to determine a variant’s clinical significance

When evaluating the variant type of a genetic alteration, one should consider whether it’s an activating mutation, whether it’s a loss of function mutation, is it a carbon number variation, or a fusion? Is it present or absent in various somatic variant population databases? What is the variant allele frequency of the genetic alteration, could it be a germline variant? If it has a 50% or 100% MAF, what is the minor allele frequency or the population frequency of this variant, what is the functional characterization of this variant? Has anybody described in functional studies and population studies, or there are any other prediction algorithms that help us understand the functionality of this mutation. And if this variant is important in any particular biological pathway.

Determine clinical impact of a variant to individual patients

The guidelines recommend the review of specific information sources to assess the clinical impact of a variant. These are FDA approved therapies, professional guidelines, well-powered studies with consensus, investigational therapies, including clinical trials, small studies with and without consensus, case reports, and pre-clinical studies. Once all of this information is collected, for every variant of the patient, the clinical impact of that variant needs to be assessed for diagnostic, prognostic, therapeutic, or preventative significance.

Evaluate the strength of curated evidence

The guidelines recommend classifying clinical evidence into four levels: A, B, C, and D, depending on from which source it has been acquired.

Level A: Sourced from FDA approved therapies and professional guidelines

Level B: Sourced from well-powered studies with consensus from experts within the field

Level C: Sourced from multiple small studies with some consensus and clinical trials

Level D: Sourced from preclinical studies, small studies, or few case reports without consensus

 

The Barrier to Variant Interpretation

As cancer genomics expands into routine clinical care, an exponential increase in NGS studies and clinical trials makes it hard for laboratories to keep up.QIAGEN has integrated the 2017 AMP/ASCO/CAP Standards and Guidelines for the Interpretation and Reporting of Sequence Variants with our deep QIAGEN Knowledge Base to enable any molecular pathology lab to quickly and confidently report both the clinical relevance of somatic variants and the associated treatment options and clinical trials available to the oncologists.

Do you need a clinical reporting solution that is highly accurate, reproducible and standardized?

If you answered yes, we invite you to watch a free recording of our webinar that demonstrates step-by-step how QCI Interpret not only automates AMP/ASCO/CAP, but gives you full transparency into the underlying evidence supporting the classification.

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