Invitae Announces Study Published In JAMA Network Open On The Largest Study To Date On Uncertain Results From Hereditary Disease Genetic Testing, The Study Evaluated Data From More Than 1.6M Individuals Undergoing Multi-Gene Panel Testing

Author: Benzinga Newsdesk | October 25, 2023 11:04am

Invitae (NYSE:NVTA), a leading medical genetics company, today announced findings from the largest study to date on uncertain results from hereditary disease genetic testing. Published in JAMA Network Open, the study evaluated data from more than 1.6 million individuals undergoing multi-gene panel testing across various clinical specialty areas. This study shares with the medical genetics community a dataset that broadly shows the prevalence and attributes of DNA variants of uncertain significance (VUS) and the approaches that help with reclassifying these variants into definitive results. These results underscore the need for detailed clinical information and results from appropriate family studies to facilitate proper interpretation..

"Uncertainty in genetic testing is frustrating for patients, clinicians and laboratories alike. Variants of uncertain significance are not actionable and are often reported from multi-gene panels, exome or genome sequencing, and other genetic tests," said Swaroop Aradhya, Ph.D., FACMG, senior study author and chief of global medical affairs at Invitae. "This study illustrates the VUS burden in hereditary disease genetic testing across clinical areas, and provides clinicians with useful observations that can inform how they educate, set expectations and manage the care of their patients. This becomes particularly important as genetic testing is increasingly incorporated into professional practice guidelines in medical specialties beyond clinical genetics. Invitae has demonstrated leadership in clinical variant interpretation over the last decade and continues to innovate relentlessly to further advance this science and reduce VUS so that more patients can receive conclusive results."

The study, titled "Rates and Classification of Variants of Uncertain Significance in Hereditary Disease Genetic Testing," found that 41% of its more than 1.6 million participants had at least one VUS. When larger gene panels were ordered, especially those intended for diagnosing rare diseases, the likelihood of identifying a VUS increased. As expected, the VUS rate went up as increasing numbers of genes were tested.

A notable finding in this study was that the prevalence of VUSs differs based on race, ethnicity and ancestry (REA), as well as by age group and clinical area. For example, Ashkenazi Jewish and White individuals had the lowest number of observed VUS per individual, while Pacific Islander and Asian individuals had the highest. Therefore, expansion of  the data used for variant interpretation to populations across the globe are needed to reduce uncertain results for historically underrepresented populations and make genetic testing equitable. In that respect, Dr. Saumya Jamuar Shekhar, M.D., clinical geneticist, KK Women's and Children's Hospital and director, SingHealth Duke-NUS Institute of Precision Medicine in Singapore and a co-author on this study, stated "This publication highlights an important need to improve variant interpretation for populations whose genomes are less understood, such as those in southeast Asia and other regions. As Singapore increasingly invests in genomic medicine to improve healthcare for its citizens, it is critical that we have the means to accurately interpret DNA variants in this population."

Uncertainty regarding a variant's clinical classification can be resolved over time when more evidence becomes available. Over the course of this study's eight-year span, a large number of VUSs were reclassified, impacting more than 160,000 individuals who had been referred for genetic testing at Invitae. Of those VUSs, 1 in 5 were resolved to clinically significant classifications, as defined in guidelines by the American College of Medical Genetics and Genomics. Clinical evidence, including detailed clinical information for the patient and results from family studies, contributed the most to VUS reclassifications. There is a critical need for clinicians to partner closely with laboratories to ensure that detailed clinical information is available for variant classification and follow up family testing is performed whenever appropriate.

Invitae has already performed genetic testing for more than 4 million individuals, and as millions more in the future are referred for genetic testing for diagnosis, screening, or research, it is imperative that sophisticated methods are developed to generate evidence that can help classify DNA variants definitively. Data from this study point to the utility of evidence from computational methods and from clinical evidence, both of which need to be gathered more broadly and consistently. As presented at various national conferences, Invitae has invested heavily in developing state-of-the-art machine learning methods to produce reliable evidence for variant classification that has already contributed to reducing uncertainty in results for more than 300,000 individuals referred for genetic testing at Invitae. 

For more information about genetic testing, visit Invitae. 

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