Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria

Read the paper

At Invitae, we believe there’s a new gold standard for genetic testing, one that includes both high-quality testing and a dedication to improving medicine by sharing data and best practices.

We recently published our approach to variant classification in Genetics in Medicine, the official journal of the American College of Medical Genetics and Genomics (ACMG). The paper describes our variant classification process, which builds on the guidelines issued by ACMG and the Association for Molecular Pathology (AMP) and represents a significant improvement in clinical genetic testing.

Why did we build on the ACMG-AMP guidelines?

Establishing a formal classification framework

While the ACMG-AMP guidelines were a major step toward establishing a common framework for variant classification, several aspects of the guidelines lack specificity or are subject to varied interpretations. Our clinical genomics group developed Sherloc: a set of semiquantitative, hierarchical evidence-based rules for locus interpretation.

How did we build on the ACMG-AMP guidelines?

Using the ACMG-AMP guidelines to classify more than 40,000 clinically observed variants, we refined the classification criteria to add greater clarity to subjective rules, and capture edge cases and exceptions.

Limitation Sherloc Solution
Certain ACMG-AMP rules conflate concepts that should be considered separately. Expands overly encumbered criteria into a set of discrete but related rules that can be weighted separately. This reduces subjectivity and increases consistency in the variant classification.
Certain pairings of ACMG-AMP rules capture types of evidence that contribute to the same basic argument, which creates a “double counting” effect. Groups evidence criteria into broader categories so that only the strongest piece of evidence from the category is counted. This prevents inflated classifications due to “double counting” weak pieces of evidence.
The “clinical criteria” style of the ACMG-AMP guidelines introduce difficulty in intuitively understanding the cumulative strength of the evidence. As a result, it is difficult to appreciate how much additional evidence is needed to move to a more definitive classification. Substitutes the “clinical criteria” style with a categorical framework and numerically weighted evidence criteria. The sum of the weighted evidence represents the strength of the argument for pathogenicity, supporting a more intuitive understanding of the evidence required for a definitive variant classification.

Example: Evidence for pathogenicity based on family segregation

In the case of family segregation, Sherloc takes a vague notion of supporting evidence that "may be used as stronger evidence” in certain situations, and distills it down into quantifiable scores that can be combined with other pieces of evidence to arrive at a final variant classification.

Accurate, clear, and open variant interpretations

Through transparency into our interpretation process and detailed methodologies, we believe we can enable better treatment and care through consistent, evidence-based variant classifications.

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