Andrew Stergachis: 'The Brotman Baty Institute Clinical Variant Database offers a practical lens on how the burden of VUS is shouldered by patients seen in practice, as well as how VUS reclassifications are – or aren’t – being communicated to patients, providers, and variant databases.'
A new peer-reviewed paper raises a critical question: Who is responsible for informing patients when the classification of their genetic variant changes?
According to the American College of Medical Genetics and Genomics (ACMG), the answer is that it is a “shared responsibility” among the ordering health-care provider, the clinical testing laboratory, and the patient. But a new analysis published in Genetics in Medicine reveals that this ‘shared responsibility’ model is falling short, failures that have the potential to impact patient care.
“Right now, the only guidance that exists states that communicating reclassifications is a shared responsibility among the patient, the physician, the hospital, and the testing lab,” said Corresponding Author BBI’s Andrew Stergachis, M.D., Ph.D. “And the challenge is that the shared responsibility is no one’s responsibility.”
The study, titled “Imprecision medicine: Systematic gaps in reporting variants of uncertain significance (VUS) and their reclassifications,” reviewed electronic health records (EHRs) and genetic testing reports from 5,158 patients seen from 2015 to 2024 at the University of Washington adult genetics clinic and the Fred Hutchinson Cancer Center genetics clinic.
Co-authors of this study include BBI-affiliated authors: Jeremy Stone, B.A., Doug Fowler, Ph.D., Lea Starita, Ph.D., and Fuki M. Hisama, M.D.
The authors found that the number of VUS reported relative to diagnostic variants can vary by over 14-fold, depending on the primary indication for genetic testing and 3-fold depending on self-reported race. Moreover, at least 1.6 percent of variant classifications used in the EHRs for clinical care are outdated based classifications in ClinVar, the NIH-funded public archive of genetic variant reports. Furthermore, in 26 cases, the testing lab updated ClinVar with a new reclassifications, but the testing lab never communicated that reclassification to the patient or provider.
“This is not a large number of individuals, but it should be zero,” Stergachis said. “We have a measurement of this unacceptable gap, and can now work toward closing it.”
The study also introduces the Brotman Baty Institute Clinical Variant Database (BBI-CVD), an EHR-linked database containing structured demographic, clinical, and genetic testing information. By aggregating data from over 20 different clinical testing laboratories, BBI-CVD provides a unique view of how VUS reporting and reclassification play out across diverse clinical contexts.
“This database offers a practical lens on how the burden of VUS is shouldered by patients seen in practice, as well as how VUS reclassifications are – or aren’t – being communicated to patients, providers, and variant databases,” said Stergachis.
Funded by a BBI Catalytic Collaboration grant and funding from the National Institutes for Health, the BBI-CVD is intended as a shared resource for researchers, clinicians, testing labs and patients.
Call to Action
The study concludes with a call to action: “It is paramount that we do not enable this shared responsibility to further deteriorate into no responsibility. If genomic precision medicine is to be broadly implemented into clinical practice, we need to move beyond a ‘shared responsibility’ and create and implement clinical systems and safeguards that best serve our patients.”
So, what are the next steps?
“This is a classic ‘last mile’ problem – ensuring that updated information on variants actually reaches the patient or provider,” said Stergachis. “We are now working with researchers, scientists, and clinicians to identify a scalable model that works in real-world settings.”
