What is a Genetic Variant?
Our DNA is organized into genes. Each gene influences different aspects of how our body develops, grows, and functions. Genes influence things like our hair color, our height, and also our risk of getting certain diseases, such as cancer or heart disease. The collection of all the genes in our body is called our “genome.” You share the majority of your genome with every other human. Each individual has enough differences in their genes to make them unique. Certain versions of specific genes, or genetic variants, can be unique to your family.
Genetic Variants and Disease
Having genetic variants is normal. Most variants will not make any difference in a person’s health. However, some genetic variants can increase or decrease the chances of disease. For example: You may have chosen to get a DNA test for variants known to cause increased cancer risk. This genetic testing would look for specific changes or types of changes in your DNA that have been studied in other families with the same disease to see if you have any variants that are known to increase disease risk. If a variant is known to cause an increased disease risk, it may be called a pathogenic mutation or pathogenic variant. If it is highly likely to cause increased disease risk it may be called a likely pathogenic (disease-causing) variant. If this is the case, your family members may be tested to see if they also have the variant. Individuals with variants that increase their disease risk can often take actions that decrease their risk; for example: individuals with genes that increase their risk of colon cancer can make regular appointments for early colon cancer screening.
Understanding Rare Variants
Most genetic variants are benign. In other words, they do not change the risk of disease. Even in genes that are known to cause specific diseases, most variants do not cause any change in disease risk. Recent advances in genetics, enabled by knowing the complete human genome sequencing, have identified common variations that change risk for most common diseases. However, new genetic variants happen every generation, so every person has rare variants that are unique to their family. There are few variants that are unique to you, and you inherited additional variants that were unique to your parents, grandparents, great-grandparents, and great-great-grandparents. Scientific studies and advanced computer algorithms allow geneticists to confidently classify some variants as benign or likely benign even if they are unique. However, if there is insufficient or conflicting evidence about whether a variant will cause disease risk, it will be initially termed a variant of uncertain clinical significance, often referred to as a VUCS or VUS.
Medical Care and VUS
The American College of Medical Genetics (ACMG) suggests that individuals with VUS should not alter their medical decisions because of their VUS. They should use family history and other risk factors do make medical decisions. For example: if an individual has a VUS in a gene known to be associated with cardiomyopathy, they should base their medical decisions entirely on other known risk factors, such as family history and diabetes. ACMG suggests that an individual with a VUS could revisit the variant every year or two to determine if there is additional information about their variant.
If there is sufficient evidence to determine if a VUS does or does not cause disease in the family, the VUS may be reclassified. It may be classified as pathogenic (disease-causing), likely pathogenic (likely disease-causing), likely benign (likely not causative), or benign (not causative). If a variant is determined to be likely benign or benign, medical decisions for you and your family members might be based on lifestyle choices and personal medical history rather than genetic risk. However, if a variant is classified as pathogenic or likely pathogenic, you will be counseled about higher disease risk and possible actions to test for or prevent future disease based on your genetic risk. Families of individuals with pathogenic or likely pathogenic variants also benefit from knowing about their relatives genetic risk. Family members who are at risk of inheriting the same variant can be tested for that specific variant and take actions to decrease their disease risk. The family members without the variant may not have any increase in disease risk.