[2023-09-22] Variant of uncertain significance
The other day, while doing research for my post on World Gynecologic Oncology Day, I read the informational brochure about genetic testing published by the European Network of Gynaecological Cancer Advocacy Groups (ENGAGe). It included references to the MSH2 gene and noted that alterations in this gene can lead to an increased risk of gynecologic cancers, notably ovarian and endometrial cancer, as well as bowel cancer. As part of the genetic testing I underwent in 2021, which confirmed that I had a mutation in my BRCA2 gene, I learned that I also had a variant in my MSH2 gene. Not surprisingly, I was a little concerned by what I was reading in the ENGAGe genetic testing brochure.
So I put in a call to the Genetics Clinic at the Children's Hospital of Eastern Ontario (CHEO), which handles genetic testing in the region and provided my results in 2021. While waiting for a call back, I did additional research and came across a September 2023 report from CHEO indicating that the particular variation I have in my MSH2 gene is still considered a Variant of Uncertain Significance. The report stated: "The available evidence is insufficient to determine the role of this variant in disease conclusively."
Today, CHEO Genetics Counsellor Kelly called me back and confirmed what I had suspected, namely that there can be multiple variants on a given gene, some known to affect gene functioning, some with unclear impacts on gene functioning, and some with no impacts on gene functioning. Kelly explained that there a five categories of genetic changes:
- Pathogenic variant (sometimes called a mutation), which is known to affect gene functioning
- Likely pathogenic variant, which most likely affects gene functioning
- Variant of uncertain significance, which may or may not affect gene functioning—the evidence is not clear
- Likely benign, which most likely does not affect gene functioning
- Benign, which is known to not affect gene functioning
My particular MSH2 variant falls into the third category—a variant of uncertain significance.
Kelly noted that there can be hundreds of variants within a gene, so two people who test positive for an alteration in a given gene (MSH2, for example) may have different variants that fall within different categories—some pathogenic, some of uncertain significance, and some benign. The ENGAGe brochure states: "Sometimes genetic tests find alterations in the genes that cannot be interpreted in a meaningful way. This occurs occasionally and is called a Variant of Unknown Significance (VUS). For most women this type of result will not have significant implications. Relatives do not need to be offered genetic testing for a VUS. No screening or prevention should be undertaken for a VUS."
Kelly encouraged me to contact CHEO every three years to check whether there has been any change in interpretation of relevant gene alterations. She noted that, most of the time, a variant of uncertain significance is reclassified to the likely benign or benign category, which I found quite reassuring.
