The Significance of Unknown Significance: A Teachable Moment

Jeanette J. McCarthy, MPH, PhD; Bryce A. Mendelsohn, MD, PhD


July 05, 2016

Bigger Issues

This case shines a spotlight on the complexities of variant interpretation, as well as the roles and responsibilities of the testing laboratory and the ordering physician. As the methodologies of genetic testing continue to evolve, several critical questions remain unanswered. What are the obligations of genetic laboratories to disclose their literature and database searches and interpretation procedures? How often should laboratories revisit variant classifications with new evidence, and how should changes in classification be communicated years later? What is the responsibility of ordering physicians to independently investigate a VUS and form their own opinions, and what proportion of physicians who order genetic tests feel competent to perform this task? Was it the responsibility of the laboratory to suggest that the parents be tested to determine whether the variant was de novo, or was it the responsibility of the healthcare professional who ordered the test?

Responsibility aside, it is a wake-up call to the entire field to become better versed in genetics and genomics, because genetic testing is here to stay. In such cases as this, it is common to consult with a genetics professional—for example, a medical geneticist or genetic counselor—to mediate the genetic testing transaction.

Key Points for Healthcare Providers

We advise healthcare providers not to discount genetic testing because of these complexities, but to be aware of some key points when ordering genetic tests and interpreting results.

  • When patient undergo most types of genetic testing, including gene sequencing and chromosomal microarrays, it is not uncommon for the test to reveal at least one variant. However, not all variants are created equal. Although some may be disease-causing, most are inconsequential. Distinguishing between these types of variants (ie, interpreting/classifying the variant or establishing the variant's clinical significance) is one of the most challenging aspects of genetic testing.

  • The clinical significance of a variant is not based on a single piece of evidence, but rather on a body of evidence that needs to be carefully weighed. Variant interpretation is somewhat subjective even when using a defined methodology, such as the ACMG guidelines. This can result in different interpretations by different laboratories. It is reasonable to expect the laboratory to have a transparent methodology for variant classification, to document the specific evidence used to classify each variant, and to share that information upon request.

  • A negative test result does not always mean that the patient does not have that genetic disease. Although most cases of Dravet syndrome carry a SCN1A mutation, some cases that are phenotypically consistent with Dravet syndrome have not had SCN1A mutations identified.[9] Many genetic diseases exhibit locus heterogeneity, where the same disease may have different genetic causes—some known, and others yet to be discovered. In these circumstances, it is difficult to rule out a genetic disease by a negative test result from a single gene.

  • A VUS is not a negative result but an indeterminate result, and should be treated as such: potentially pathogenic or benign. Counseling the patient regarding the possibility of finding a VUS before testing is a sound practice. Some laboratories report VUS findings; others either do not report them or do so selectively. There are potential risks either way. When ordering a test, the physician should ask the laboratory to clarify whether VUS results will be returned. If they are, the urge to assign more or less meaning to the result than is warranted by the available data should be resisted.

  • Variant interpretation is based on information that is available at the time of testing. Over time, as more information becomes available, a classification may change, especially for a VUS. When selecting a laboratory, policies regarding how often they reclassify variants should be reviewed, as well as their procedures for notifying physicians when a laboratory result changes. Someday, electronic health records may aid in storing and tracking VUS results.

  • Awaiting data from other patients to better classify a VUS can take years. Several steps can be taken immediately by healthcare providers or motivated patients; these include additional literature searches, more detailed phenotyping of the patient (eg, imaging), testing the parents or relatives, and continuing the search for another genetic or nongenetic etiology. Some laboratories are now offering parental testing free of charge to attempt to clarify a VUS.

  • For healthcare providers who are not comfortable finding information about genetic testing or interpreting results, consulting with a genetics professional, such as a medical geneticist or genetic counselor, is a good idea.

  • GeneReviews is an excellent resource for learning about the testing and management of genetic diseases.

Any views expressed above are the authors' own and do not necessarily reflect the views of WebMD or Medscape.


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