What Is a Genomic Variant?
The Human Genome Project determined the DNA sequence (order of base pairs) of the entire human genome. Humans are 99.9% identical at the level of base pair ordering, but the 0.1% difference contributes to disease risk. Upon completion of the human genetic blueprint, research turned to (https://www.clinicalgenome.org/) identifying and cataloguing genomic variation as well as determining the clinical relevance of variants.
Genomic Variants in Oncology
A variant is an alteration (https://www.cancer.gov/publications/dictionaries/genetics-dictionary) in the most common DNA sequence. They can be classified in a number of different ways but are often based on the type of DNA error. Some variants, like a simple base substitution, have no functional significance (i.e., protein synthesis is not affected). Those that affect protein synthesis are functionally significant in oncology (https://www.ons.org/genomics-taxonomy/genomics-taxonomy-terms-table-contents).
How Variants Are Classified
Variations or variants can be tumor specific (somatic) or ones that an individual is born with (germline). Germline and somatic variants are considered biomarkers. The term variant is increasingly being used in place of the term mutation.
Individuals born with a known pathogenic variant (PV) are at increased risk for cancer. Classification and reporting of variants for inherited conditions (germline variants) has been established (https://doi.org/10.1038/gim.2016.40).
Germline variants are also classified according to pathogenicity (how the variant is associated with disease). A variant or DNA alteration may be (https://www.ons.org/genomics-taxonomy/genomics-taxonomy-terms-table-contents) benign, pathogenic, or of unknown significance. Determining the pathogenicity of germline variants is critical to inform about future cancer risks and to make recommendations for cancer surveillance and risk-reducing interventions.
Somatic or tumor variants can be classified as drivers or passengers. A driver somatic variant is oncogenic and provides an unregulated growth advantage to the cell. Passenger variants do not contribute to oncogenesis. Somatic variants are classified (https://doi.org/10.1016/j.jmoldx.2016.10.002) according to (https://doi.org/10.1038/gim.2015.47) their level of clinical significance or actionability. For somatic variants, clinical actionability is an important distinction from variant pathogenicity. A somatic variant may be a strong driver (e.g., pathogenic or oncogenic) but not actionable, in that it has no approved targeted therapy.
A four-tier framework (https://doi.org/10.1016/j.jmoldx.2016.10.002) categorizes somatic variants in cancer. Tier I lists variants with strong clinical significance in either diagnosis, prognosis, or treatment and are included in clinical practice guidelines. For example, a BRAF V600 somatic variant predicts response to the FDA-approved BRAF inhibitor targeted therapy vemurafenib. Variants of potential clinical significance are classified as tier II, variants of unknown significance as tier III, and benign or likely benign as tier IV.
Oncology nurses must learn the terminology and classification of germline and somatic variants as important biomarkers and recognize that the term mutation is outdated and is increasingly replaced with the term variant.