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When a doctor or genetic counselor orders a genetic test, the intent is to determine if their patient has a change in a specific gene that could explain their symptoms or that has been passed down through their family. Changes in genes, or mutations, can alter the function of a gene and therefore all mutations have the potential to cause disease. When analyzing a gene, laboratory scientists must decide which mutations are likely to be harmless (benign) and which are likely to be disease-causing (pathogenic).

Some mutations are easy to classify as pathogenic or benign because they are well-studied and have been found in many other patients with the same disease. However, many gene changes lack the data and frequency necessary to make a clear decision about their pathogenicity. A variant of uncertain significance (VUS) is a genetic change whose clinical impact is not yet well understood, either because it’s effect on the gene is unknown, or because there have not been enough families reported with the change. Therefore, it cannot be clearly classified as benign or pathogenic. 

Each genetic testing laboratory has a team of “variant curation” experts with access to medical literature and databases that enable them to explore the pathogenic potential of each variant. After reviewing all of the available data, these experts use their best judgment to classify the variant into one clinical impact category: pathogenic, likely pathogenic, uncertain, likely benign, or benign. Different laboratories sometimes disagree with one another about the classification of a particular variant. Furthermore, the available data changes rapidly, so a VUS may even be reclassified years after the initial report. For example, a mutation that is initially determined to be a VUS may later be reclassified as benign, or as pathogenic. Efforts are underway to centralize this data and recontact patients whose VUS has been reclassified. Until a VUS is reclassified, providers and patients may not know how to interpret this information. 

If a patient has a pathogenic mutation in a gene that increases their lifetime risk of cancer, such as BRCA1 or BRCA2, doctors will recommend cancer surveillance and possible preventative surgery. However, if the patient has a VUS in one of these genes, then it is less clear whether these measures should be taken. It is generally not recommended to make any significant medical decisions, such as surgery, after finding a VUS. Patients are advised to continue surveillance and wait for more data from the labs. This can be concerning for parents or those hoping to conceive, because patients with a VUS in an autosomal dominant gene such as BRCA1 or BRCA2 have a 50% chance of passing it on to each of their children. 

Preimplantation genetic testing for monogenic disorders (PGT-M) with in-vitro fertilization (IVF) is available for patients who desire a pregnancy and wish to screen their embryos for a specific pathogenic mutation. This technology can decrease the chance of having a child with a disease-causing mutation. However, PGT may not be available for a VUS at all fertility clinics or laboratories. Since IVF with PGT can be difficult and costly, clinics must seriously consider all of the potential issues of offering testing for an embryo with a VUS. If a VUS later becomes reclassified as benign, for example, then PGT may have been unhelpful in reducing the risk for the disease of concern. Alternatively, if the VUS is truly pathogenic then PGT may be a good option for families. 

The delicate nature of this decision may be more clear when thinking through an actual case scenario. A young Filipino woman has a history of breast cancer. Her genetic testing reveals a VUS in BRCA1. She does not yet have children, but she wishes to conceive children who will not have an increased risk of breast cancer. She meets with a genetic counselor about whether PGT is available for her. The genetic counselor discusses the pros and cons of performing PGT for a VUS. It is more common to find a VUS when testing a person who is not Caucasian because there is less data available to researchers to help them understand whether a mutation is truly pathogenic. The determination of VUS may simply be because of lack of data. More information and testing may be needed to determine whether this patient would be a good candidate for PGT. The genetic counselor can research the VUS in available curation databases and may recommend testing for the VUS for other living relatives in the family, particularly any other relatives who have had cancer. If the laboratory and the medical team have sufficient evidence that the VUS is the likely cause of the disease in the family, then they may support the patient’s desire to explore PGT. 

It is important for patients to fully understand the risks and benefits of performing PGT for a variant of uncertain significance. Genetic counselors with knowledge of variant curation can help guide patients as they explore whether PGT is an available and appropriate option for their family planning.