Interpretation of Genetic Test Results

What is a variant?

A variant is any difference in an individual’s DNA sequence when compared to a reference sequence. Variants can range from changes involving just one or a few base pairs (a substitution of one single DNA base letter for another, for example), to alterations involving long stretches of DNA (deletion of an entire portion of a gene, for instance). Only a very small amount of DNA varies between any two humans- about 0.1%.

But as the human genome is huge – 3 billion base pairs – even a 0.1% variation means that there are 3 million sites of variation between any two individuals. The vast majority of these variants are said to be silent, meaning that they do not have any biological relevance. Many variants are involved in expression of unique traits between individuals, and are responsible for differences in appearance or other heritable traits. Very few variants, perhaps only a small handful in any one individual, are associated with genetic disease.

Many variants are common in the general population – a variant that is present in more than 1% of the population is called a polymorphism. Mutations, on the other hand, are defined as variants that are present in less than 1% of the population. Generally speaking, the more rare a variant, the more likely it is to be disease-causing. Variants may exhibit different frequencies in different ancestral populations. A disease-causing variant that is rare in most of the world’s populations but more common in a particular ancestral population is called a founder mutation.

How are variants analyzed?

With the vast degree of variation in the human genome, analyzing DNA sequencing data can be a daunting task. Claritas Genomics utilizes a combination of state-of-the-art software, well-vetted algorithms, and clinical expertise to sort through millions of DNA variants in order to isolate particular disease-causing variants that are likely to be responsible for a patient’s clinical symptoms. Sometimes, an identified variant will have been previously associated with disease in the medical literature and are known to be pathogenic. For variants that haven’t been reported in the medical literature, several parameters can serve as clues as to whether a variant is pathogenic. Examples of these parameters include a variant’s gene location, population frequency, and effect on protein function.

Our ability to assess and catalog DNA variants will improve over time. As more and more patients have their DNA sequenced, databases that link a patient’s genomic data (genotype) with clinical signs and symptoms (phenotype) will become larger and more refined. This underscores the critical importance of continued research to further ascertain genotype-phenotype correlations.

What are possible results?

For a whole exome, gene panel, or single gene DNA sequencing test, there are five ways in which Claritas classifies and reports variants:

  • Pathogenic variant: Based upon previous reports in the scientific literature and information in gene variant databases, this variant is a recognized cause of some or all of the patient’s clinical signs and symptoms (the patient’s phenotype).
  • Likely pathogenic variant: This is a novel (previously unreported) variant, but based on its gene location and the predicted effect on protein function, it is likely to be the cause of some or all of the patient’s phenotype.
  • Benign variant: Based upon previous reports in the scientific literature and information in gene variant databases, this variant is recognized as a benign (not harmful), neutral variant and is not responsible for the patient’s phenotype.
  • Likely benign variant: This is a novel variant, but based on its gene location and predicted lack of effect on protein function, it is likely to be benign and not responsible for the patient’s phenotype.
  • Variant of uncertain significance (VUS): Based on current evidence, it cannot be determined if this variant is pathogenic or benign. Some VUSes have been previously reported in the scientific literature but the evidence associating them with disease may be conflicting. Other VUSes are novel variants whose effect on protein function cannot be predicted. Claritas makes a concerted effort to further classify VUSes as new evidence emerges, and will notify the ordering health care provider if new information becomes available about a VUS that changes its classification. Testing parental samples can sometimes be useful to help assess the clinical significance of a VUS. If a VUS is not inherited from either parent, then this VUS is generally thought to be pathogenic. But many genetic specialists argue that this alone isn’t enough to state that the VUS causes the disorder. Likewise, if the parent carries the same VUS but does not have the same genetic disorder, then many would say that the VUS must be benign. However, due to possible reduced penetrance or variable expressivity, others argue that this isn’t enough to say that the VUS is benign. In some cases, Claritas Genomics offers free parental testing to help with the interpretation of VUSes.