WHAT YOU DIDN’T KNOW
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 more than half of positives reported to patients are false positives due to inaccurate variant interpretation (This is when the data are averaged across many different hereditary diseases and different genetic testing laboratories). Application of more robust evidence requirements and methodology is likely to fix this problem. This is CGI’s humanitarian 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 relatively 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 well 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 I AVOID FALSE POSITIVES?
Unfortunately, it is challenging for the patient, genetics consumer or clinician to be completely discerning in their choice of a genetic testing company for any given genetic test. Key factors that contribute to this are:
- Only recently has the “accuracy” of clinical variant interpretation methods become partially measurable.
- For the majority of genetic tests offered to patients and consumers, the clinical genetic variant interpretation accuracy of the tests falls outside of regulatory safeguards.
- Where regulation does have oversight of clinical genetic variant interpretation, the focus of the regulation is generally on reproducibility rather than clinical accuracy.
- Clinicians ordering tests for patients are frequently unable to order from their preferred testing company due to a variety of externally imposed restrictions, including insurance reimbursement or institutional policy.
- A patient receiving a clinical genetic test rarely has control or knowledge of where their sample is sent for testing.
It is unlikely that a patient can completely avoid receiving a potential false positive genetic test result. For this reason, CGI offers Variant FactChecker™ to patients once they have received a positive genetic test. CGI’s Variant FactChecker™ provides an independent, research-use-only, high-stringency second opinion on a variant’s classification.
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 VUSs will ultimately be discovered to be benign, with only a minority of VUSs proving to be pathogenic. Even in very sick patients or families with evidence of inherited disease, 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 VUSs in their test result increases. Some laboratories or companies no longer report VUSs.
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 with these paid services:
- Variant FactChecker™ can be used for an independent research-use-only evaluation of a VUS. Variant FactChecker’s™
the 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® later 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 VUSs 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 current families and future families with the same VUS. Thus, every variant solved saves generations.