Refinements to existing guidelines establish a more detailed and transparent approach for classifying variants at scale
As genetic testing grows both more complex and more integrated into mainstream medical care, continually improving how genetic variants are classified as pathogenic, benign or unknown is essential. Researchers with Invitae Corporation (NYSE: NVTA), one of the fastest growing genetic information companies, have developed and validated a new framework that refines genetic variant classification guidelines, resulting in a more complete and consistent approach that can be reproduced across genetic testing laboratories. Featured in the October print issue of Genetics in Medicine, the variant classification framework could increase consistency in classification industry-wide.
“The utility of genetic information for patients and clinicians depends on genetic variants being accurately and consistently classified. Existing guidelines were a major milestone toward achieving that goal. Our approach further refines the use of those guidelines, adding greater clarity in areas of subjectivity and better reflecting uncommon cases and exceptions,” said Robert Nussbaum, MD, chief medical officer of Invitae. “We believe in a comprehensive and transparent approach that includes both high-quality testing and a dedication to sharing data and best practices.”
The new approach was developed using an iterative process that began with the introduction of the 2015 American College of Medical Genetics (ACMG)-Association of Molecular Pathologists (AMP) framework. Invitae classified more than 40,000 clinically observed variants under the ACMG-AMP guidelines. As the guidelines were applied to case after case, areas requiring additional specificity or those open to ambiguous or contradictory interpretation were identified. Meeting weekly, Invitae researchers systematically developed a scalable and consistent approach to overcome these challenges across a large clinical variant-interpretation team. The result is a system that includes more than 100 refinements to the ACMG-AMP guidelines to improve variant classification across individuals and laboratories.
The resulting system, Sherloc, consists of a set of semiquantitative, hierarchical evidence-based rules for locus interpretation that are designed to ensure confident and consistent variant classifications. Each variant is evaluated for five broad categories of evidence, in a hierarchical process that ensures comprehensive review of all the evidence. When data is available, score-based criteria are applied by well defined, specific rules. The data supporting pathogenicity, and the relative strength of that data, are transparent and auditable for each variant. Moreover, Sherloc sets pre-determined, score-based thresholds that, corresponding to the AMP-ACMG guidelines, reduce individual biases and help to prioritize variants falling just short of pathogenicity but are often reclassified as pathogenic based on family testing and/or additional published evidence.
“As with any emerging area of science, continually refining clinical and laboratory techniques is essential, as is validating those approaches so the results are consistently reproducible. Sherloc establishes an approach that does both,” said Keith Nykamp, PhD, lead author on the paper and head of variant interpretation at Invitae. “Overall, Sherloc has proven to be highly adaptable, efficient, and consistent across multiple disease areas and a large variant interpretation team. It adheres to the guidelines, but also illustrates the specific application and evolution of the ACMG-AMP criteria in a clinical molecular laboratory. We are hopeful that by publishing our approach to variant interpretation, Sherloc may be useful to others in the field of variant interpretation and clinical genomics. That is why we deliberately chose not to copyright our approach or claim intellectual property; instead, we invite others to use the interpretation framework.”
The full paper can be found in the current print issue or in the advance online publication of Genetics in Medicine.
Invitae Corporation (NYSE: NVTA) is one of the fastest growing genetic information companies in the United States. Invitae Corporation's mission is to bring comprehensive genetic information into mainstream medical practice to improve the quality of healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit our website at invitae.com.
Safe Harbor Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements that the company’s variant classification framework could increase consistency in classification industry-wide and may be useful to others in the field of variant interpretation and clinical genomics. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: risks associated with the company’s ability to use rapidly changing genetic data to interpret test results accurately and consistently; laws and regulations applicable to the company’s business; the company’s history of losses; the company’s ability to compete; and the other risks set forth in the company’s filings with the Securities and Exchange Commission, including the risks set forth in the company’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2017. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements.
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Source: Invitae Corporation