In each newsletter, we give participants the opportunity to have their questions addressed by experts in the field. This question was addressed by Georgia Wiesner, MD, MS, a nationally renowned clinical cancer geneticist, who is an Ingram Professor of Cancer Research, Professor of Medicine in the Division of Genetic Medicine, and the Director of the Clinical and Translational Hereditary Cancer Program for the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. If you have a question you would like addressed, please email the ICARE team at ICARE@inheritedcancer.net for consideration in future newsletters.
Q. How common is it for a genetic test result to be downgraded from a positive result to an uncertain result?
A. A pathogenic (or ‘positive’) test result means an individual has been identified with an inherited cancer gene mutation that places them at higher cancer risk. However, the issue of a positive result being downgraded was recently highlighted in The Wall Street Journal about a family who was tested in 2015 and found to have a positive BRCA2 mutation that was later interpreted in 2019 as an uncertain result. Unfortunately, the knowledge of the mutation had prompted multiple family members to have preventive surgeries  which may not have been necessary. Downgrading of a positive test result to a variant of uncertain significance (VUS; unknown cancer risk) or a benign result (no increased risk for cancer) is very uncommon. In fact, a recent study by our group of 338 patients who had a positive result on cancer susceptibility testing showed that only 2% were downgraded to a VUS . The majority of variant reclassifications are for uncertain results being downgraded to benign. Ultimately, these findings highlight the need for laboratories to share variant classification data, so it is easily accessible to everyone, including other laboratories. There are several websites with searchable databases of variant classification (ncbi.nlm.nih.gov/clinvar/ and clinicalgenome.org); however, this remains an issue as some laboratories will not share this data with the public. The American College of Medical Genetics (ACMG) continues to call on these laboratories to end the practice of maintaining proprietary classification databases and to begin publicly sharing this data . When a test result is reinterpreted, a new report is issued by the laboratory and the ordering provider is notified. If you have been told that you have a positive (pathogenic) test result, it is very unlikely that this interpretation will change in the future.