In each newsletter, we give participants the opportunity to have their questions addressed by experts in the field. This question was addressed by Rebecca Smith, PhD, Laboratory Director at Genetics Associates, Inc. with over 20 years of experience in biomedical research and 7 years of experience in clinical laboratory diagnostics. If you have a question you would like addressed, please email ICARE@inheritedcancer.net for consideration in future newsletters.
B. How is a genetic variation (or DNA change) classified as pathogenic or benign?
A. Genetic variation, or DNA changes between people, is a normal part of being human. Each person’s DNA contains roughly 4 to 5 million normal genetic variations (sometimes referred to as ‘single nucleotide polymorphisms’). Humans are 99.9% alike, with only ~0.1% variation. Genetic testing labs interpret an individual’s DNA change by comparison to a reference sequence, and then figure out if the change is harmful versus harmless.
Trained laboratory geneticists interpret DNA changes through various sources, including review of several databases. This is like a detective working to find enough evidence to “make a case” that the variant is “harmful” or “harmless.” All sources of evidence are not equal and can be scored as supporting, moderate, strong, very strong, or stand-alone. Types of information to classify variants include: type of change (e.g., truncating, missense, splicing, etc.), predictions made through computer programs, whether the DNA change tracks with the occurrence of cancer in family members (referred to as ‘family segregation studies’), whether the variant is seen in many unrelated patients with the same disease, and how common it is in the population (i.e., more common suggests it may not be harmful). For example, a genetic variant found in more than 5% of the general population can be assigned stand-alone benign (harmless) evidence.
After researching all the available information for a variant, the evidence scores are added up to determine the variant’s final classification. A five-tier classification system has been developed, ranging from “pathogenic”, “likely pathogenic”, “uncertain significance”, “likely benign”, and “benign”.1 Insufficient or conflicting evidence may result in classifying a change as a variant of uncertain significance (VUS).
While the identification of genetic variants has been simplified through advances in technology and the use of automated tools, the interpretation of changes remains a challenge. However, sharing classification evidence across databases and making this information publicly available improves our ability to interpret changes which in turn helps us to better counsel and treat patients.
1Richards, et al. Genet Med. 2015 May. PMID: 25741868.