ICARE Newsletter Summer 2020

Ask the Expert

In each newsletter, we give participants the opportunity to have their questions addressed by experts in the field. This question was addressed by Georgia Wiesner, MD, MS, a nationally renowned clinical cancer geneticist, who is an Ingram Professor of Cancer Research, Professor of Medicine in the Division of Genetic Medicine, and the Director of the Clinical and Translational Hereditary Cancer Program for the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. If you have a question you would like addressed, please email the ICARE team at ICARE@inheritedcancer.net for consideration in future newsletters.

Q. How common is it for a genetic test result to be downgraded from a positive result to an uncertain result?

A. A pathogenic (or ‘positive’) test result means an individual has been identified with an inherited cancer gene mutation that places them at higher cancer risk. However, the issue of a positive result being downgraded was recently highlighted in The Wall Street Journal about a family who was tested in 2015 and found to have a positive BRCA2 mutation that was later interpreted in 2019 as an uncertain result. Unfortunately, the knowledge of the mutation had prompted multiple family members to have preventive surgeries [1] which may not have been necessary. Downgrading of a positive test result to a variant of uncertain significance (VUS; unknown cancer risk) or a benign result (no increased risk for cancer) is very uncommon. In fact, a recent study by our group of 338 patients who had a positive result on cancer susceptibility testing showed that only 2% were downgraded to a VUS [2]. The majority of variant reclassifications are for uncertain results being downgraded to benign. Ultimately, these findings highlight the need for laboratories to share variant classification data, so it is easily accessible to everyone, including other laboratories. There are several websites with searchable databases of variant classification (ncbi.nlm.nih.gov/clinvar/ and clinicalgenome.org); however, this remains an issue as some laboratories will not share this data with the public. The American College of Medical Genetics (ACMG) continues to call on these laboratories to end the practice of maintaining proprietary classification databases and to begin publicly sharing this data [3]. When a test result is reinterpreted, a new report is issued by the laboratory and the ordering provider is notified. If you have been told that you have a positive (pathogenic) test result, it is very unlikely that this interpretation will change in the future.

[1] Marcus. WSJ. 2019 Dec. Available at: https://tinyurl.com/wksxknr; [2] Turner, et al. Genet Med. 2018 Jun. PMID: 29875428; [3] Marcus. WSJ. 2020 Jan. Available at: https://tinyurl.com/rpvq692

ICARE Featured Video May 2020

Variant Classification

Below you may watch a featured video from the May 2020 Genetics Case Conference, which focused on deciphering variant reports and classification with guest expert Dr. Rebecca Smith from Vanderbilt University Medical Center.



ICARE Newsletter Summer 2019

Ask the Expert

The following question was addressed by Gillian Hooker, PhD, ScM, LCGC, who is the president-elect for the National Society of Genetic Counselors, Adjunct Associate Professor in the Division of Genetic Medicine at the Vanderbilt University Medical Center, and the Vice President of Clinical Development for Concert Genetics in Nashville, TN.

Q. Why was the BRCA1/2 mutation detected through genetic testing ordered by my healthcare provider but not found on my 23andMe® genetic test?

A. This is not unexpected. There are thousands of different mutations in the BRCA1 and BRCA2 (BRCA1/2) genes found among families with inherited cancers. When testing is ordered by a healthcare provider, the vast majority of mutations in these genes can be detected if they are there.  However, BRCA1/2 at-home genetic testing done by 23andMe® looks for only 3 specific mutations in the BRCA1/2 genes found mostly in people of Ashkenazi Jewish descent. This testing does not look for the thousands of other mutations that have been found in the BRCA1/2  In fact, a study published last year looked at 49 different patients who learned from at-home testing that they had mutations.1 When these samples were tested again after a healthcare provider ordered the test, 40% of the mutations were not found (i.e., they were ‘false positives’).  Other “mutations” were present, but turned out to be benign, non-harmful genetic changes after further inspection. These findings highlight the shortcomings of at home genetic testing, and the potential for miscommunication, misinformation, and distress as eloquently articulated in a recent article by Dorothy Pomerantz.2 We recommend reaching out to your doctor or a genetic counselor if you have questions about these tests.

1Tandy-Connors, et al. Genet Med. 2018 Dec. PMID: 29565420.
2Pomerantz D. “23andMe had devastating news about my health. I wish a person had delivered it.” Stat News, available at: https://www.statnews.com/2019/08/08/23andme-genetic-test-revealed-high-cancer-risk/

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 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.