ICARE Newsletter Winter 2019

Testing Interpretation and Variant Reclassification

Results of germline genetic testing generally yield three types of test results: Deleterious (positive), Negative (no mutation detected), and Variant of Uncertain Significance (VUS). As more genes are tested, the chance for a positive result goes up, as does the chance of receiving a VUS result.1 VUS results tell us that it remains uncertain whether the test result is positive or negative. A recently published study demonstrated that most VUS results are downgraded to negative over time.2 Specifically, of more than 25,000 VUS results reported through a single testing laboratory, about a quarter were reclassified over time, of which over 90% were downgraded to negative (benign or likely benign). Information from this study is important when counseling patients with VUS results, informing them that most VUS results that are reclassified are downgraded, and explaining that VUS results are generally not used to direct medical care. On the topic of interpretation of genetic test results, another paper reported on a novel method to better classify BRCA1 mutations as positive or negative, through tracking how cells with specific BRCA1 changes, growing in lab dishes, respond.3 These types of efforts are important to better classify gene changes identified through genetic testing, and hopefully will serve to reduce the number of VUS results received by patients in the future. Finally, as knowledge expands, it becomes more important to make interpretation of genetic test information widely available for it to be maximally used to improve patient care. To that effect, a recent report outlined a global resource that includes data on more than 20,000 unique BRCA1 and BRCA2 variants, called the “BRCA Exchange”.4 Over 6,100 variants in this database have been classified by an expert panel, and approximately 3,700 are established to be positive (i.e., they raise the risk for cancer). This dataset was set up to pull in information from existing clinical databases, including the Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database, as well as other databases and data worldwide. It has a single-point-of-access website (https://brcaexchange.org/) and serves to demonstrate that this type of widespread data sharing across multiple entities is possible for other inherited cancer genes and genes associated with other diseases.

1Kurian AW, et al. JAMA. 2018 Aug 1. PMID: 29801090.
2Mersch J, et al. JAMA. 2018 Sept 25. PMID: 30264118.
3Findlay GM, et al. Nature. 2018 Oct. PMID: 30209399.
4Cline MS, et al. PLoS Genet. 2018 Dec 26. PMID: 30586411.




ICARE Newsletter Summer 2013

Sharing BRCA Test Results with Adolescent and Young Adult Children—What Does the Latest Research Show?

While there are specific recommendations against BRCA testing for minors,1 guidelines are less clear about whether parents should share their own test results with their children. Because there are no recommended surveillance or risk reduction options prior to age 25 for known BRCA mutation carriers, there has been debate about balancing the benefits of sharing parents’ test results with the possible negative psychosocial outcomes. The largest published study on this topic included 253 parents who had undergone BRCA testing and their reports of sharing test results with children, ranging in age from ages 10 to 25. Of the 505 children, parents shared test results with 66%. For those who shared true negative results, children often expressed relief. However, the authors encourage parents to take this opportunity to discuss the continued benefits of positive health behaviors (e.g., diet, physical activity); despite decreased cancer risk based on BRCA test results. Importantly, parents sharing BRCA positive or variant of uncertain significance results perceived distress more frequently than those sharing negative results.2 Parents considering sharing test results with children may benefit from consultation with a genetic and/or other health care professional with expertise in family communication to help ensure that information is presented in a way that is age-appropriate, helps to reduce distress, and achieves positive psychosocial and behavioral outcomes.

1. Borry P, et al. Clin Genet 70:374-81, 2006. 2. Bradbury AR, et al. Cancer, 2012.




ICARE Newsletter Summer 2011

Ask the Expert

We are fortunate to have Dr.  Alvaro Monteiro, who is a molecular geneticist and expert on the BRCA1 and BRCA2 genes, as a member of our team. For our first ICARE newsletter, Dr. Monteiro teaches us about Variants of Uncertain Significance.

Q. What is a Variant of Uncertain Significance (VUS) test result? How do researchers learn more information about variants?

A. A variant of uncertain significance test result is when a change is found in the tested DNA for which there is no clear answer to determine if the change leads to an increased risk of developing cancer. To determine whether a particular variant is linked to increased cancer risk, researchers use a series of tools that include studying families with the variant (to determine whether the variant tracks with cancer), comparing the gene code in different species (for example dog, mouse, chicken and fish) to determine the importance of this particular area in the gene (important areas of the gene stay the same with different species), computer programs, and functional tests that study how the gene may work (or not work) with the variant.