Sherloc was developed through an iterative process using the ACMG–AMP guidelines as a starting point. The ACMG–AMP draft guidelines were released for member comment in August 2013 and adopted for internal use at Invitae. A working group was formed comprising American Board of Medical Genetics and Genomics–certified laboratory directors, doctoral-level scientists, and American Board of Genetic Counseling–certified genetic counselors with experience in many clinical areas of diagnostic genetic testing, including hereditary cancer, cardiology, neurology, and pediatric genetics.
The working group interpreted variants observed during diagnostic testing by using the implemented framework, and identified variants for which (i) strict adherence to the framework led to classifications at odds with the established understanding of clinical significance, or (ii) uncertainty or disagreement arose about the correct application of the rule set. The working group met weekly to discuss these cases, identify the underlying genetic issues, and refine the rules and their valuations. This iterative process continued for more than two years and through more than 40,000 unique variants identified during clinical laboratory testing across more than 500 genes and conditions. The framework has developed through many major and minor iterations. The rule set described herein is Sherloc version 4.2. All interpreted variants are routinely deposited into ClinVar.7 (link)