When a "Disease-Causing Mutation" Is Not a Pathogenic Variant

The clinical utility of molecular genetic testing relies on our accurate and comprehensive knowledge about the relationships between genes/variants and diseases/symptoms. Correctly interpreting the clinical significance of detected variants continues to be a constant challenge for molecular diagnostic practice. This challenge has become substantially magnified as testing based on next generation sequencing (NGS)3 becomes rapidly integrated in routine clinical practice.Whole exome sequencing for clinical diagnostics is a new practice. There are many challenges that lie ahead. One key issue out of many remains our ability to correctly interpret the clinical significance of gene variants, which lags far behind our ability to discover them. Consequently, many variants are currently categorized as variants of “unknown significance” in a clinical report. This certainly poses a challenge to physicians who receive the report, but we would argue that an even more pressing issue is the possibility of a false diagnosis: a non–disease-causing variant being interpreted as a pathogenic variant owing to our incorrect knowledge about gene/variant and disease/symptom associations. This possibility may be small for tests based on single genes or gene panels but markedly higher for tests based on whole exome sequencing/whole genome sequencing. Assigning a non–disease-causing variant as causative to a patient will deny the patient the future opportunity for identifying the real disease causation, and as a result the patient may never receive a truly correct disease diagnosis. Any such false diagnosis has the potential to have a huge impact on the care of the individual patient, on the diagnosis and management of family members who test negative or positive for the false-positive variant, and potentially on future family planning.DNA sequence variants can largely be grouped into 2 categories: truncating variants and nontruncating variants. Truncating variants consist of nonsense variants, out-of-frame indels, most splicing variants, and partial gene …