Genetic Test Results Change Faces

As a part of my Molecular Genetic Pathology fellowship, we experience a clinical component to training in addition to all of the laboratory training we receive. This last month, I rotated through Cancer Genetics, where genetic counselors discuss genetic testing with patients with a personal or family history of cancer. The counselors describe the process of genetic testing and help chose genetic tests to look at the patient’s risk for an inherited cancer syndrome.

Patients are looking forward to the certainty that will come from a genetic test, because it is the wave of the future and they think you can learn so many things from your genetics. The truth, however, can be much less clear. Up to 30% of people receive a Variant of Uncertain Significance (VUS) as their genetic test result. This rate increases as larger panels are test more genes.

Figure 1. A set of genes and associated cancer types tested by a hereditary cancer genetic test. (Taken from Myriad MyRisk Gene Table.)

A VUS represents a variation in a person’s gene that doesn’t have enough information to say that it is benign or pathogenic. This gray zone is very uncomfortable and confusing for patients and providers alike. There are several cases where someone acted on a VUS as if it were a pathogenic variant and ended up having radical interventions like a bilateral mastectomy.

We know that as scientific and medical knowledge increases, our ability to reclassify these variants improves. For laboratories, this means periodic reanalysis of previously reported variants. If this process is not properly set up, it can be very laborious and extensive. Furthermore, not only was a timeline for variant reanalysis unknown, but also the likelihood of variants becoming upgraded or downgraded had not been described.

Two recent studies helped provide some answers to these questions. The first, published in JAMA, comes from the cancer genetic group I was working with, led by Dr. Theo Ross M.D. Ph.D., worked in conjunction with Myraid (Lab that first started testing the BRCA genes, and now tests many more) to determine how often variants were reclassified. Looking at 1.1 million individuals tested at Myriad, the average time to reclassification for a VUS was 1.2-1.9 years (Mersch J et al Jama 2018). Additionally, 90% of VUS were downgraded to benign/ likely benign representing 97% of patients with a VUS. This figure from the paper shows how the time to issuing a reclassification (amended report) has decreased (Figure 2).

Figure 2. The time to sending an amended report is shown by the year the report was first issued. From Mersch et al. JAMA 2018.

I worked on the second study, which looked at variant reclassification in childhood epilepsy genetic testing (SoRelle et al JAMA Peds 2019). The results, published in JAMA Pediatrics, also found most patients had a VUS reclassified to benign/likely benign. However, several clinically significant changes (reclassified to or from pathogenic/ likely pathogenic) occurred as well (Figure 3).

Figure 3. Patients with reclassification of gene variants from each category. Arrows that cross the red line represent an instance where a change in diagnosis would result from variant reclassification. Seven patients had both a pathogenic or likely pathogenic variant and VUS reclassified and are only represented once.

Furthermore, there was a linear relationship between the time the test was reported and the rate of variant reclassification (Figure 4). We found that 25% of patients with a VUS would experience a reclassification within 2 years.

Figure 4. Reclassification rate is plotted as the fraction of reclassified variants for each year testing was performed (VUS= black line, pathogenic or likely pathogenic= red line). Solid lines represent patients with a reclassified result and dotted lines are extrapolated slopes.

Overall, the conclusions of the two studies are somewhat similar:

  1. Most patients with a VUS experience a downgrade reclassification to likely benign or benign.
  2. Variant reclassification should be performed at least every 2 years
  3. Rates of reclassification may differ by disease type. Investigation by a similar study design should be performed in other genetic diseases.

References

  1. Mersch J, Brown NPirzadeh-Miller SMundt ECox HCBrown KAston MEsterling LManley SRoss T. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320:1266–1274.
  2. SoRelle JA, Thodeson DM, Arnold S, Gotway G, Park JY. Clinical Utility of Reinterpreting Previously Reported Genomic Epilepsy Test Results for Pediatric Patients. JAMA Pediatr. 2018 Nov 5:e182302.

-Jeff SoRelle, MD is a Molecular Genetic Pathology fellow at the University of Texas Southwestern Medical Center in Dallas, TX. His clinical research interests include understanding how the lab intersects with transgender healthcare and advancing quality in molecular diagnostics.

Personal Genome Testing and You

The recent events with 23andme and the Food and Drug Administration have brought personal genomic testing into the spotlight. In case you haven’t been following the case, the FDA wrote a warning letter to 23andme—a company that will access various points on your genome and give you the results for around $99—that basically states that because the tests diagnose, mitigate, or prevent disease they require regulatory clearance. The FDA also said false positive results for certain breast or ovarian cancer markers could lead to unnecessary preventative surgery.

Since receiving the letter, 23andme as stopped marketing their genetic testing service. At this writing I’m not aware of the status of ongoing testing or if the company is still accepting new samples. 23andme has 15 working days from the date of the letter—which would be 12/13—to let the FDA know how they’re working to resolve the noted issues.

How does this affect laboratory medicine? On the face of it, not that much. Yes, clinical laboratory scientists and pathologists could lose their jobs of the 23andme labs were forced to close their doors. The field of personal genome testing is a relatively new one—23andme began testing in 2008—but even so, it’s important to realize that this type of testing can positively affect laboratory professionals and pathologists.  More laboratories equal more jobs, after all, and not just for bench techs and pathologists, but for consultants, inspectors, and administrators as well. I know that I’ll be watching to see how this plays out.

-Kelly Swails