8.4 Interpreting Genetic Test Results

Variant Classification

Previously, pathogenic changes in the genome were called mutations (GECKO, n.d). More than 1% of the general population carries benign changes, which are referred to as polymorphisms (GECKO, n.d). Laboratories vary in how and what is reported. However, most accredited/licensed laboratories in Canada follow the American College of Medical Genetics and Genomics (ACMG) guidelines [PDF] (Richards et al., 2015). This is a five-tier system of classification of genomic variants. The ACMG classification framework organizes each of the criteria by the type of evidence (e.g. population data, functional data) as well as the strength of that evidence (e.g. very strong, strong, moderate, supporting) (Richards et al., 2015).

The ACMG classifications are recommended for describing pathogenicity in patients with suspected hereditary disorders, primarily Mendelian. This classification system is not meant to apply to somatic variants, pharmacogenomic variants, or complex disorders (Richards et al., 2015).

The five classifications of gene variants are:

• Pathogenic: The variant is responsible for causing disease. Ample scientific research supports an association between the disease and the gene variant. These variants are often referred to as mutations.
• Likely pathogenic: The variant is probably responsible for causing disease, but there is not enough scientific research to be certain.
• Variant of uncertain significance (VUS or VOUS): The variant cannot be confirmed to play a role in disease development. There may be insufficient scientific research to confirm or refute a disease association or conflicting research.
• Likely benign: The variant is probably not responsible for causing disease, but there is not enough scientific research to be certain.
• Benign: The variant is not responsible for causing disease. There is ample scientific research to disprove an association between the disease and the gene variant.

Evaluation needs to be done for each variant. Just because a gene is associated with a disease does not mean that all variants in that gene are pathogenic. Additionally, a variant must be evaluated for all diseases with which it is thought to be associated. A pathogenic variant for one disease is not necessarily pathogenic for a different disease. It is important to re-evaluate variants periodically; the classification of a variant can change over time as more information about the effects of variants becomes known through additional scientific research.

A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the test’s purpose, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic variant, identify an increased risk of developing a disease (such as cancer), or suggest further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, healthcare providers typically cannot use a positive test result to predict the course or severity of a condition. Rarely test results can be false positive, which occurs when results indicate an increased risk for a genetic condition when the person is unaffected.

A negative test result means that the laboratory did not find a change that affects health or development in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic variant, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing or re-testing at a later date may be required to confirm a negative result. Rarely, test results can be false negative, which occurs when the results indicate a decreased risk or a genetic condition when the person is affected.

In some cases, a test result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been confirmed to play a role in the development of disease, known as a variant of uncertain significance (VUS or VOUS), it can be difficult to tell whether it is a natural polymorphism or a disease-causing variant. For these variants, there may not be enough scientific research to confirm or refute a disease association or the research may be conflicting. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result.

While many more genetic variants can be identified with whole exome and whole genome sequencing than with select gene sequencing, the significance of much of this information is unknown. Because not all genetic changes affect health, it is difficult to know whether identified variants are involved in the condition of interest. Secondary findings are a part of the analysis performed but are not related to the reason the test was performed in the first place (National Society of Genetic Counsellors, 2023). Incidental findings are also unrelated to the initial reason for testing but are detected unexpectedly (National Society of Genetic Counsellors, 2023).

In 2013, then again in 2017 and 2021, the American College of Medical Genetics and Genomics (ACMG) recommended that all labs performing whole exome and whole genome sequencing tests report particular secondary findings, in addition to any variants that are found related to the primary purpose of the testing. In the 2021 updated recommendations, ACMG proposed a list of 81 genes that are associated with a variety of conditions, from cancer to heart disease. The 81 genes for which secondary findings are reported were chosen because they are associated with conditions that have a definable set of clinical features, the possibility of early diagnosis, a reliable clinical genetic test, and effective intervention or treatment. The goal of reporting these secondary findings to an individual is to provide medical benefit by preventing or better managing health conditions. The variants that are reported are known to cause disease. Variants of unknown significance, whose involvement in disease at the current time is unclear, are not reported.

The information provided by secondary findings can be very important because it may help prevent a disease from occurring or guide the management of signs and symptoms if the disease develops or is already present. However, as with any type of medical diagnosis, the news of an unexpected potential health problem may lead to additional health costs and stress for individuals and their families. On the basis of secondary findings, additional testing to confirm results, ongoing screening tests, or preventive care may be advised. Individuals receiving whole exome or whole genome sequencing can choose to “opt out” of analysis of the 81 secondary finding genes and not receive variant results. As whole exome and whole genome sequencing become more common, it is important for individuals to understand what type of information they may learn and how it can impact their medical care.

Nursing Implications

Nurses play a pivotal role in supporting patients undergoing genetic testing by providing comprehensive patient education, facilitating informed consent, and fostering shared decision-making. They ensure patients understand the purpose, potential outcomes, and implications of genetic tests, addressing emotional and ethical considerations. Nurses guide patients in evaluating options and preparing for the results, promoting autonomy and informed choices. They collaborate closely with genetic counselors and geneticists, referring patients for specialized consultations when necessary to enhance care quality and optimize health outcomes. This interdisciplinary approach ensures patients receive holistic, informed, and compassionate care throughout the genetic testing process. Nurses need to be aware of the scope, responsibilities, and accountabilities of other members of the genomics healthcare team so they can appropriately refer patients (CDC, 2024).

The Role of Genetic Counselors

The National Society of Genetic Counselors (National Society of Genetic Counsellors, 2023) recommend individuals have counseling before obtaining genetic testing to plan how results will be returned, including secondary or incidental findings. Genetic counseling before genetic testing can help decide who is the right person in a family to get a genetic test and can help ensure the right tests are ordered. Genetic counseling after genetic testing can help patient’s understand their results. Large-scale genetic tests can have findings unrelated to why the test was ordered in the first place.

Attribution & References

Except where otherwise noted, content on this page is adapted from Do all gene variants affect health and development? , What do the results of genetic tests mean? , What are whole exome sequencing and whole genome sequencing? and What are secondary findings from genetic testing? In Help Me Understand Genetics by MedlinePlus, Public Domain

• Nursing implications section written by Andrea Gretchev, CC BY-NC 4.0

References

CDC. (2024, May 15). Genetic testing. Genomics and your health. https://www.cdc.gov/genomics-and-health/about/genetic-testing.html

Genetics Education Canada: Knowledge Organization (GECKO). (n.d.). GECKO on the run: Genomic test results. https://www.geneticseducation.ca/resources-for-clinicians/genomic-technologies/genomic-test-results/gecko-on-the-run

Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., Rehm, H. L., & ACMG Laboratory Quality Assurance Committee (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine, 17(5), 405–424. https://doi.org/10.1038/gim.2015.30