Courtagen Life Sciences Blog

Pathogenic, Benign, or Uncertain: Evaluating Genetic Variants

Posted by Cheryl Scacheri, MS, LGC on Jan 5, 2017 2:03:00 PM

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When we do a genetic test at Courtagen, we read thousands to millions of letters of the patient’s DNA sequence to identify variants, But that is just step one. We then review many pieces of information to understand the meaning of those variants.

To make a genetic diagnosis, we look for DNA variants that are likely to affect a gene product (usually a protein or enzyme), causing it to change or not be created at all. If you think of DNA as a recipe, we are looking for differences that may significantly impact the final product. For example, using baking soda instead of baking powder when making a cake will significantly impact what ultimately comes out of the oven. This also happens in DNA. If one part of the recipe for a protein or enzyme is off, it can cause disease.  

Variant Classifications

Since not all variants cause disease, we classify classify them in three general categories:

  • Pathogenic and likely pathogenic. Variants that Courtagen considers to be pathogenic or likely pathogenic have significant and often multiple lines of evidence indicating that they are associated with the disease. Pathogenic variants are rarely found in the general population.
  • Benign and likely benign. These are variants that tend to be common in healthy people or have other significant lines of evidence showing that they are unlikely to cause a disease. Each of us has about 10 million benign variants, so we find a lot of these with our tests!
  • Variants of uncertain significance (VUS). Most of the variants in this category do not yet have enough evidence to be considered pathogenic or benign or there are conflicting lines of evidence. As more information is learned, a VUS may be classified as benign or pathogenic.  

Some of the information we use to classify variants  is available in databases and scientific publications. Other, equally critical, pieces of information—such as a detailed description of the patient’s symptoms and family history—must be provided by the ordering clinician or patient. Each piece of information or line of evidence is important to the test results we generate. Variant analysis is highly complex, and Courtagen has a team of geneticists and genetic counselors with advanced degrees  and others who have undergone extensive training who work on this aspect of the testing.

Many of the variants we find in a patient’s DNA are so rare we don’t have a lot of information about them. As we’ve written about previously, when we find one or more variants in a patient’s genes, knowing if it is also present in a parent gives us valuable information. Sometimes scientific advances shed new light on variants we’ve found in a patient, and we can change the report to reflect this new information.

What makes a variant likely to cause a disease?

  • The variant has been seen in people with the condition, but not in people who don’t have it
  • Inheritance, or lack of inheritance, fits with the family history
  • The variant changes, or fails to make, the gene product, which is usually a protein or enzyme

Variant Information in Courtagen Reports

We communicate information about variants to clinicians through our report, which includes:

  • A detailed interpretation for pathogenic, likely pathogenic, and rare variants of uncertain significance that match the patient’s symptoms
  • Recommended next steps, including parental testing of variants (if parent samples were not provided), other follow-up testing, genetic counseling, and clinical correlation by the physician, as appropriate.
  • Detailed descriptions of all rare genetic variants identified and references from the scientific literature, in the Extended Variant List
  • For all pathogenic and likely pathogenic variants, we include the pieces of evidence used in variant scoring, as described by the guidelines from the American College of Genetics and Genomics, in the Extended Variant List

For more information about Courtagen's Genetic Testing, contact us using the form on this page. 

Topics: Genetic Testing, Genetics