New tool puts reproductive risk for BRCA carriers into perspective

“I just wish someone had told me this was a possibility.”

Kara Maxwell, MD, PhD, distinctly remembers the moment she heard those words eight years ago from the mother of a child with Fanconi anemia (FA). Maxwell met her at a conference focused on the rare, recessive genetic bone marrow disorder that causes myriad medical challenges, including childhood cancer. While survival is improving, the average lifespan for FA is currently only 20 to 30 years.

FA is an inherited disorder that can happen when both parents carry mutations in certain genes associated with cancer risk, including BRCA1 or BRCA2. The woman that Maxwell met was a BRCA2 gene mutation carrier. She told Maxwell that she wouldn’t have changed anything about her pregnancy, but she just wished she’d been made aware of the fact that—in addition to personal cancer risks and the potential of passing down a gene mutation to their children—BRCA gene mutations can also create entirely new genetic issues, if two carriers have a child together.

“If one of my patients is already dealing with the difficult news of learning they’re a BRCA mutation carrier, I don’t ever want them to be surprised by having a child with an even more difficult diagnosis,” Maxwell said.

The risk is rare and nuanced. It takes a geneticist or a licensed genetic counselor to unravel and explain the probabilities. But, until recently, professionals did not have a comprehensive tool to reference for such discussions. In November, Maxwell, an assistant professor of Hematology-Oncology and Genetics, and her team published a resource for genetic professionals to help counsel individuals with cancer-related genetic mutations, like BRCA1/2, about reproductive risks.

A primer on cancer genetics

BRCA genes are among the most well-known genes linked to hereditary cancer risk. An individual with a mutation in the BRCA1 or BRCA2 gene has an increased lifetime risk of developing breast, ovarian, pancreatic, or advanced prostate cancer. These gene mutations are passed down through families. Men and women of all races and ethnicities can have a BRCA gene mutation, though they’re most common among certain groups, notably those of Ashkenazi Jewish ancestry.

But BRCA genes aren’t the only genes linked to an increase cancer risk. Cancer genetic testing typically involves a multi-gene panel test that also looks for mutations in other genes. For example, mutations in the genes MLH1, MSH2, MSH6, or PMS2, are linked to Lynch Syndrome, the most common cause of hereditary colorectal cancer.

“Everyone should take stock of their family cancer history and talk to their doctor to find out if genetic testing is recommended,” said Susan Domchek, MD, executive director of the Basser Center for BRCA at Penn Medicine. “If someone receives genetic testing and learns that they carry a cancer gene mutation, it may also have a major impact on their reproductive decision making.”

How cancer gene mutations affect reproductive planning

By definition, inherited gene mutations can be passed down to one’s children. A parent who has a mutation in a cancer risk gene has a 50 percent chance of passing it on to each of their children, and a 50 percent chance of passing on the normal copy of the gene. Men, as well as women, can inherit and pass on a mutation in a cancer risk gene to either a son or a daughter.

If both parents carry a mutation in a cancer risk gene, then not only does their child now have a 75 percent chance of inheriting the mutation, but the combination of the damaged genes can create new problems, in the form of life-shortening disorders that typically begin to cause symptoms in childhood. For example, in addition to childhood cancers, FA can cause developmental abnormalities, abnormal thumbs and/or facial features, and kidney dysfunction.

However, BRCA1/2 and other cancer risk genes haven’t traditionally been part of the carrier screening panels that are typically offered as part of standard reproductive planning.

“So, if you’re a genetic counselor talking to someone newly diagnosed as a carrier for a cancer risk gene mutation, how do you help them decide how much effort—time, money, resources, emotions— to spend on getting genetic testing for their partner? That’s the question we set out to answer,” Maxwell explained. “It’s not a simple decision, because testing for cancer risk genes is not free, and it requires effort and input.”

A tool to help inform reproductive counseling for cancer gene mutation carriers

Maxwell’s team created a resource that helps to put these risks into perspective. Their paper provides estimates across different genetic ancestries of the risk of being a carrier for a genetic variant that causes life-limiting severe pediatric syndromes, and the risk of your child actually having one of these conditions, if you’re also a carrier of the same mutation.

For example, if you’re a BRCA2 mutation carrier and your partner is of Latin American genetic ancestry, their risk of being a BRCA2 mutation carrier in the absence of family history is approximately 1:231 (0.4 percent) and so your risk of having a child with a pediatric disease caused by two BRCA2 gene mutations is about 1:923 (0.1 percent). Putting it into context, Maxwell notes, that’s a similar level of risk to having a child with Down syndrome at age 30 (about one in 1,000).

“This tool is valuable from the genetic counseling perspective. It provides clear, concise data tables you can use to quickly compute a more precise risk estimate for a potential pediatric condition occurring in offspring in the context of being a carrier of a single gene mutation," said first author Jacquelyn Powers, MS, LCGC, associate director of Genetic Counseling for the Cancer Service Line at Penn Medicine. “We hope this tool will increase and enhance reproductive risk discussions with adults who have hereditary cancer predisposition syndromes.”

Empowering patients with the data to make personal choice

What BRCA carriers and their partners decide to do with this information will look different for everyone. Some couples will decide it’s worth it to move forward with genetic testing for their partner. Others will feel relieved by low odds and decide it’s not necessary. Some people will feel reassured simply to have a better understanding of all the possibilities. Others may decide to explore options like preimplantation genetic testing to ensure their children do not inherit a cancer risk gene mutation.

“All of these reproductive decisions are layered with so many personal choices,” Maxwell said. “We want people to feel like they have all of the information they need to make those choices.”