How we classify genetic variants when interpreting patients results

Published on March 5, 2016

In genetic diagnostics, variant classification forms the basis for clinical judgment. Despite the international guidelines and principles, there is still significant inter-laboratory variation in classification of genetic variants. A wrong classification can misguide the clinical judgment in patient care including severe consequences in risk stratification among family members. Blueprint Genetics is dedicated to full transparency in diagnostics and this includes our variant classification strategy. Our clinical statements provide all the evidence behind our variant classification. We believe this is critical information for a health care professional who makes clinical decisions based on the test result. Blueprint Genetics submits to ClinVar all variants we classify to help other patients and to enhance the development of the field.

Founded in sound practices, built by the best

Blueprint Genetics has developed a variant classification scheme primarily intended to classify variants in rare monogenic disorders. Our scheme closely follows the guidelines and interpretation criteria established by the American College of Medical Genetics and Genomics (ACMG 2015), the industry standard for clinical genetic diagnostics laboratories. Our scheme has been validated with over 3000 rare disease patients and evaluated by several clinical geneticists and genetic counselors around the world. Our specialized team of geneticists and clinicians critically evaluate the existing literature, variant databases, reference databases, and our in house built knowledge and mutation databases to establish the classification of variants and to provide a clinical statement. Our follow-up report service ensures that all re-classified variants will be reported to previous patients tested positive for them.

Systematic, clear, and sensible variant evaluation criteria 

Variants are evaluated using evidence from population and gene/disease-specific databases, in silico prediction tools, our in-house variant database, and the appropriate scientific literature. To this end, we use points to evaluate variants for potential pathogenicity, with evidence from the relevant databases and literature as the foundation for scoring.

Assigning evidence-based points ensures all evidence is assessed and that the decisions made by our entire variant review team are as accurate, traceable, and consistent as possible. The use of points does not imply quantitative certainty in our evaluation. Rather, it establishes an objective checklist for assessing all of the available evidence.

Download a white paper: A guide to understanding variant classification

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