The results of multiplex genetic cancer tests are being interpreted in different ways at different laboratories, even when they are Clinical Laboratory Improvement Amendments (CLIA)–approved commercial laboratories.
A new study has found considerable variation: In some cases, genetic mutations were interpreted as pathogenic or likely pathogenic by some labs but were considered to be of unknown significance by others. These variations could have implications for medical management decisions, the authors comment.
"In clinical practice, there is the need to counsel individuals undergoing genetic testing that there might be results with conflicting interpretation," lead author Judith Balmaña, from Vall d'Hebron Institute of Oncology, Barcelona, Spain, told Medscape Medical News.
The study was published online September 12 in the Journal of Clinical Oncology.
Progress, But More Work Lies Ahead
For the study, the research team, with senior author Susan M. Domchek, MD, from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues, analyzed multiplex panel genetic cancer susceptibility test results for non-BRCA genes reported to the Prospective Registry of Multiplex Testing (PROMPT).
Their analysis focused on 518 individuals with 603 genetic variants who had test results interpreted by more than one approved commercial laboratory.
Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. For most variants (74%), different laboratories interpreted the results in a consistent manner. But for 155 (26%) of the detected gene variants, interpretation of their significance differed among the reporting labs.
Fifty-six of the 518 individuals (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, which could alter medical management.
"We should aim to decrease this percentage of genetic findings with conflicting interpretation since many medical management decisions for the person being tested and his/her family members rely on this interpretation," Dr Balmaña said.
Approached for comment, Peter J. Hulick, MD, MMSc, medical director, Center for Personalized Medicine, NorthShore University HealthSystem in Evanston, Illinois, said the findings are "not surprising to me as a clinical geneticist [and] not unexpected for those in the genetics community."
"On the surface, an 11% rate of discrepancy of classifications that could impact management is alarming, but considering where we started from in terms of understanding human variation in our genome and how it affects risk, we have come a long way. There's still more work to be done but the direction is positive," Dr Hulick told Medscape Medical News.
He said there has been "tremendous effort to reduce variability of interpretations between testing labs. ACMG [American College of Medical Genetics and Genomics] is working very hard at this issue. Progress is being made," he added.
One Piece of the Puzzle
Dr Balmaña and colleagues say the discrepancies between commercial laboratories in interpretation of variants in cancer-related genes found in the study seem largely based on differences in the interpretation of evidence. "The lack of a gold standard test for pathogenicity, or a noncontroversial interpretation of functional analyses, suggests that discrepant interpretation of challenging variants, particularly missense and splice-site variants, will persist for some time," they predict.
Dr Balmaña told Medscape Medical News that cancer risk estimation "should rely on different risk factors, including genetics and family history. In this regard, genetics is one piece in the puzzle to estimate someone's cancer risk, provide adequate screening or preventive measures and it should aim to decrease uncertainty."
Dr Hulick agrees. "Like any medical test, one needs to look at the big picture," he said. "Genetics is one piece of the puzzle, and we have to overlay this information over other clinical parameters. The study underscores the need to have providers who understand the limitations and be able to interpret the nuances of genetic testing."
"Many patients and physicians believe that genetic testing offers a simple 'yes/no' answer, but it can be more complicated. This article helps highlight this issue to an audience that are not necessarily genetics experts but certainly rely on results from inherited cancer genetic tests to make clinical decisions," Dr Hulick said.
The study had no commercial funding. Several authors disclosed relationships with various pharmaceutical companies, as listed in the article.
J Clin Oncol. Published online September 12, 2016. Abstract
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