New Study Concludes That Genetic Testing Is Not as Final as We Thought

Genetic testing has become an important medical standard for families with known histories of hereditary disease. Genetic tests identify “changes in chromosomes, genes, or proteins. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. More than 1,000 genetic tests are currently in use, and more are being developed.” Individuals who choose to go through the mental and emotional process of taking a genetic test and absorbing the potentially life-changing conclusions may be disturbed to find out that results of such tests are not always consistent.

According to a study entitled "Prevalence of Variant Reclassification Following Hereditary Cancer Genetic Testing" by Jacqueline Mersch, MS, CGC1; Nichole Brown, MS, CGC1; Sara Pirzadeh-Miller, MS, CGC1; et al, genetic tests involving hereditary cancer can result in eventual amended variant reclassifications as time goes by. "In this retrospective cohort study that included 1.45 million individuals and 1.67 million initial tests, 59,955 amended reports were issued due to variant reclassification. Among variants initially classified as uncertain significance, 7.7% were reclassified, of which 91.2% were downgraded to less severe classifications and 8.7% were upgraded to more severe classifications. Reclassification of variants initially classified as pathogenic or benign was rare," notes the report findings.

The significant differentiation in test results was mostly discovered in patients with unique mutations. More commonly, initial results indicating that patients had more severe forms of cancer were downgraded into less severe potential diagnoses. In other cases, 8.7% of patients who were informed that their risk factors were minimal were eventually told that their new results held more severe consequences.

Dr. Theo Ross, Professor of Internal Medicine and senior author of the study quotes that "if a variant is reclassified to being pathogenic, then it matters to the patient. For example, if they have a broken Lynch syndrome gene, then they need different care from their doctor such as having colonoscopies at an earlier age or more frequently - sometimes as often as every year. Or, if they have a broken BRCA gene, they may want to have prophylactic surgery or add MRI scans to their mammogram screening program."

Many patients who receive severe test results choose to begin treatment, find support groups, and have their extended family tested for the same mutations. Eventually learning that their results were not so severe can have a detrimental effect on mental health as well as disjoint the sense of community some are able to find in support groups. “For families this can be a major social issue,” offered Dr. Park, clinical director of the advanced diagnostics laboratory at Children's Medical Center in Dallas. “There are support groups centered around certain genes. Now they are no longer part of that group.”

"We are getting new data all the time. We may identify new families that have an inherited susceptibility to cancer and learn something from their DNA,” continued Dr. Ross. “Labs may determine the atomic structure of the protein product of the gene with the variation and see an abnormal shape or find that cells with the variant gene don't behave as expected. With collective familial, biochemical, and functional data all pointing to abnormal, a variant is reclassified from "variant of uncertain significance" to "pathogenic".

One patient referenced in a New York Times report, Rick Garrison, a 61-year-old Denton, Texas resident, was initially diagnosed with “Lynch-like syndrome”. Essentially, Mr. Garrison was told that he may have Lynch syndrome, but he also may not. His doctors suggested annual check-ins to monitor potential progress of the disease, including colonoscopies, endoscopies, and whole skin exams.

Years later, in June of 2018, Mr. Garrison was contacted by the testing lab to be informed of new research results in other patients, implicating that he was most certainly a carrier of Lynch syndrome. This news turned his life around, causing both constant monitoring for cancer symptoms as well as illuminating the necessity of his extended family’s need to be tested for the mutation. ‘He will change his plans to retire next year because he worries about the cost of health insurance for someone with Lynch syndrome. Instead he will keep his firefighter job, which comes with insurance, and wait until he is 65 to retire and get Medicare.“Cancer will probably get me in the end,” he said. “But because of this, I probably will have a few more good years.”’

On either end of the spectrum, knowing that genetic test results could prove inaccurate is a difficult development for those with hereditary disease potential. “The implications of this study are three-pronged. Physicians need to be aware of how rapidly knowledge about gene variants is advancing and that reclassifications are common. Labs need to review gene variant information on a regular basis and alert physicians to changes. Finally, patients and their family members need to be made aware of reclassifications by their physicians so they can make well-informed choices," Dr. Ross suggested.