Clinical Variant Analysis for Cancer – Applying AMP Guidelines to Analyze Somatic Variants
Analogous to the ACMG guidelines for germline mutations, the Association for Molecular Pathologists (AMP) has issued guidelines to assess and report on somatic variants. The key paper in this area was published by Li et. al (2017) with the title “Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer – A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists”. This chapter, as well as chapters 3 and 4, are based on this paper, which I recommend reading for further detail. You can find the full reference in the bibliography.
It turns out that the clinical reporting across labs in the US varies substantially in some areas in terms of what is actually being reported. In a survey that included 67 responses, it was interesting to see to what degree labs differed from each other in terms of the level of detail included in their reports. The majority of the participants (83%) used gene panels as their diagnostic vehicle ranging from less than a dozen to slightly below one hundred genes. To a lesser degree, some labs employed clinical exome (12%) or whole genome (5%) based tests to conduct their analytics work. Nearly all of the labs reported on SNVs and indels (95%), whereas CNVs and gene fusions were only reported on in about a third of the labs (35% and 37% respectively).
The most striking findings were the following (see also Fig 1 on page 10):
- Numerical cutoff for Minor Allele Frequencies (MAF): Most labs (< 75%) use ‘1%’ as the cutoff to define what constitutes a minor allele. This is important as this metric constitutes what is considered a rare mutation.
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