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HCI and U Researchers Help Create Genetic Database to Aid Doctors

BRCA Exchange

Recently, Huntsman Cancer Institute and University of Utah researchers Sean Tavtigian and David Goldgar were involved in a global project to compile as much data as possible on variants of two genes called BRCA1 and BRCA2 into a single database called the BRCA Exchange. Variations of the genes can increase the risk of breast and ovarian cancers, among others.

Image from iOS (2)Both Tavtigian and Goldgar have worked on BRCA genes since before they were discovered in the 1990s, and have evaluated several variants of the genes since their discovery.

As we’ve talked about in the past, changes to the code in DNA are what lead to cancer—although not all do.

Most people are probably familiar with a representation of DNA as something approximating a twisted ladder. 

If you get really specific, you can see the chemical composition of DNA. It’s made of phosphates, sugars called deoxyribose, and 4 nucleic acids (called adenine, cytosine, thymine, and guanine). Together, we call the phosphates and deoxyribose molecules the sugar phosphate backbone. In all the sketches in this article, the sugar phosphate backbone is the red part, while the nucleic acids are in blue.
Image from iOS (1)


Image from iOSThe representation of DNA that’s most useful when talking about gene variants is somewhat of a simplification of this very specific model. The part we’re interested in is the nucleic acids, the names of which are shortened to the first letter—As, Cs, Ts, and Gs. They pair up in very specific ways: As with Ts and Cs with Gs.

DNA doesn’t actually do anything by itself, but your cells use it as a recipe to build proteins, which carry out nearly every function inside a cell. So if there’s an error in the DNA, the proteins (which are also combinations of As, Cs, Ts, and Gs) come out weird. They might do something different. They might not work at all.

A metaphor sometimes used is a sentence. Take this one:



I ate cotton candy.


Assume that sentence is the protein. A mistake in the DNA could result in an addition or a change in the protein that makes it say something different.


I hate cotton candy.


Other errors in DNA could make a protein (or a sentence) that just doesn’t work at all.


I ate cotton cand.


The proteins that are made from the recipes in the BRCA1 and BRCA2 genes have important functions, as it turns out. The proteins made from them repair mistakes in DNA. DNA gets damaged all the time. Biology has a very accurate mechanism to fix the damage, and that mechanism includes the proteins made based on the BRCA genes. If repair doesn’t happen, the damage can sometimes lead directly to cancer. The proteins from BRCA1 and BRCA2 are called tumor suppressors. Off versions of the proteins made using variants of them can make cancer more likely.

Our little drawing shows a scrap of DNA with 4 pairs of As, Cs, Ts, and Gs. These pairs are called base pairs. BRCA1 and BRCA2 have many, many times more base pairs than that—leaving room for many variants.

Some BRCA variants can increase the risk of cancer. Some don’t seem to be associated with disease at all. Doctors and patients can’t just know if they have a variant of one of the genes. They also need to know what it means.

Doctors have been ordering tests of BRCA variants since 1996. Many people—women and men alike—are tested for genetic abnormalities in these genes. These tests have continued to identify variants for which little is known about whether they increase the risk of cancer. In other cases, patients have variants which don’t seem to be associated with disease. Because they have a variant, however, sometimes they are overtreated. In still other situations, patients have variants which are believed to modestly effect the risk of disease. The information available to doctors about these genes can sometimes be confusing and inconsistent.


How the Exchange Helps

The BRCA Exchange allows doctors to look up a variant of BRCA1 and BRCA2 genes that a patient might test positive for. They can then use that information to inform their decisions about preventing cancer. Until now, this amount of data had never been collected in one place.

Using the database, doctors and researchers search for variants to find out whether they’re the type of variants that cause the proteins made from their instructions to not work in the way they typically do.

For example, a patient might have a BRCA2 variant called c.7322delG. That confusing name communicates exactly where and what the change is: a deletion of the letter G (aka the nucleic acid guanine) at the 7,322nd position in one of the gene’s strands of letters. If a doctor looks it up in the BRCA Exchange right now, it will tell them that this change is “pathogenic” and that it is “predicted to encode a truncated non-functional protein”. In other words, the variant is known to be associated with an increased risk of cancer because the protein made from the BRCA2 variant’s instructions is shorter than it’s supposed to be and doesn’t work.

The BRCA Exchange contains information about more than 20,000 unique BRCA1 and BRCA2 variants. More than 7,000 of those variants have been evaluated based on their ability to increase the risk of cancer. Of those that have been evaluated, approximately 3,700 are known to be related to disease.

Collecting this amount of information required collaboration from hundreds of distinct parties and organizations, including partial databases already in existence, doctors, clinical laboratories, and researchers.

The BRCA Exchange was actually created with several purposes in mind:

  • Help doctors by creating a single database in which gene variants can be searched for.
  • Minimize confusion by evaluating every BRCA variant under the same set of criteria.
  • Speed up the process of evaluating gene variants in cases where researchers are still uncertain about the risk associated with them.
  • Encourage other similar efforts at data sharing.

Stephen J. Chanock, the director of the National Cancer Institute’s Division of Cancer Epidemiology and Genetics says the project proves large-scale collaboration and data sharing are possible. He also says such collaboration is urgently needed.

“Dr. Goldgar and I have been excited to see discoveries we contributed to in the 1990s translated for the benefit of patients and their at-risk relatives,” said Tavtigian. “Yet the problem of classifying sequence variants observed during clinical testing has proven difficult. Solutions to this problem will be accelerated by the world-wide data sharing effort the BRCA Exchange is going to enable, resulting in greater benefit to patients around the world.”



“BRCA1 Gene - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/gene/BRCA1.
“BRCA2 Gene - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/gene/BRCA2.
Burn, John, et al. “BRCA Challenge: BRCA Exchange as a Global Resource for Variants in BRCA1 and BRCA2.” PLOS Genetics, 26 Dec. 2018, doi:10.1371/journal.pgen.1007752. 
“chr13:G.32355173:TG>T.” BRCA Exchange, 15 Jan. 2019, brcaexchange.org/variant/188868.
“Huntsman Cancer Institute Helps Develop BRCA Exchange to Inform Understanding of Cancer Risk by Aggregating Data on Thousands of BRCA1 and BRCA2 Mutations.” Huntsman Cancer Institute, 9 Jan. 2019, huntsmancancer.org/newsroom/2019/01/hci-helps-develop-brca-exchange.php.
Ogino, Shuji, et al. “Standard Mutation Nomenclature in Molecular Diagnostics Practical and Educational Challenges.” Journal of Molecular Diagnostics, vol. 9, no. 1, Feb. 2007, pp. 1–6., doi:10.2353/jmoldx.2007.060081.

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