WHAT YOU NEED TO KNOW AS YOU TREAT YOUR PATIENTS
Genetic diagnostic testing for hereditary diseases saves the lives of many thousands of patients each year and is revolutionizing clinical care. However, no diagnostic test is ever perfect. Scientists have recently estimated that averaged across many different hereditary diseases and different genetic testing laboratories, more than half of positives reported to patients are false positives due to inaccurate variant interpretation. Application of more robust evidence requirements and methodology is likely to fix this problem, which is CGI’s non-profit mission.
WHAT IS VARIANT INTERPRETATION?
A genetic test is much more than just “reading” the letters of your DNA. The “reading” of your DNA letters is a fairly accurate science. However, scientists then have to make sense of your DNA letters and determine if any of the different forms of “spelling” will increase your risk for inherited disease or early death. This step is called “interpretation,” or “classification.” As clinical science advances, some previously classified variants may change classification over time. This is called “reclassification.”
HOW DO FALSE POSITIVES HAPPEN IN VARIANT INTERPRETATION?
Clinical science is never perfect, and newer scientific fields tend to be less understood than more established fields. Variant interpretation is a relatively new clinical science. The good news is that accurate genetic variant interpretation is advancing rapidly. Many scientists are already questioning previously accepted variant interpretation methods, and some scientists are working to develop better methods. However, continuous improvement is expensive, and few laboratories can fund such improvement efforts while also driving down testing costs for patients. Additionally, an insufficient talent pool of experienced clinical interpretation scientists is unable to meet the growing demand among competing genetic testing companies. Also, because variant interpretation science is advancing so quickly, it is likely that many genetic testing companies are not even aware of potential improvements they could make. CGI has formed as a non-profit and non-competing company to fix these problems.
CAN A CLINIC AVOID FALSE POSITIVES?
Unfortunately, it is challenging for a clinician to be completely informed or discerning in their choice of a genetic testing company for any given genetic test. Key factors that contribute to this are:
- Variant interpretation methodology “accuracy” has only recently become partly measurable.
- New tests are continually coming online, with non-standardized ways of reporting quality metrics.
- Where regulation does have oversight of clinical genetic variant interpretation, the focus of the regulation is generally on reproducibility rather than clinical accuracy.
- Externally imposed restrictions, including insurance reimbursement or institutional policy, restrict the clinician’s ability to select their preferred testing laboratories.
- A patient receiving a clinical genetic test rarely has control or knowledge of which company their sample is sent to for testing.
While it is unlikely that a practice can avoid receiving false positive results for patients due to inaccurate variant interpretation by the originating laboratory, once a report is issued, CGI offers Variant FactCheckerTM. CGI’s Variant FactCheckerTM provides an independent, research use only, high stringency second opinion on a variant’s classification. This service is generally patient paid, although practice or institutional payment models can be arranged with CGI.
WHAT IS A VARIANT OF UNCERTAIN SIGNIFICANCE (VUS)?
A variant of Uncertain Significance, or VUS (sometimes abbreviated VoUS), is a genetic variation for which the clinical significance is unknown, uncertain or disputed. The vast majority of VUS will ultimately be discovered to be benign, with only a minority of VUS proving to be pathogenic. Even in very sick patients, and/or families with disease running through the family, the likelihood that a patient’s VUS is the cause of illness is very low. As genetic test offerings incorporate more genes into each test, the chance that a patient will receive one or more VUS in their test result increases. Some laboratories or companies no longer report VUS.
CAN CGI HELP WITH MY VUS(s)
Most laboratories providing genetic testing do not offer robust VUS reclassification research programs. For patients not able to access an active VUS reclassification program, CGI can help in these ways with these paid services:
- Variant FactChecker™ can be used for an independent research-use-only evaluation of a VUS. Variant FactChecker™’s greatest value is for second opinions on positive variants, though a second opinion on a VUS may be helpful for patients concerned about the original report’s variant interpretation accuracy, or if the initial report is older than six months and the originating laboratory does not regularly support variant interpretation updates for their patients.
- CGI Concierge Service™ can be used for patients eager to explore more aggressive research on their VUS in hopes of driving towards a variant reclassification.
- CGI will be launching VUSolve® in 2019. VUSolve® is an advanced co-segregation based research service focused on tracking variants through families to drive data towards a potential variant reclassification. Not all VUS are well suited for this research method. Check back for further details in 2019.
When a VUS is sufficiently studied to achieve a reclassification, that reclassification applies to all other families with the VUS, and all future families with the same VUS. Thus, every variant solved saves generations.