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Genetic Testing Challenges in Oncology: Patient Told Genetic Test was Negative Turns out to be MAP Carrier

 Precision Oncology News and My Gene Counsel have partnered to produce the "Genetic Testing Challenges in Oncology" series to highlight real-world issues that genetics experts and medical professionals are encountering as genetic tests are increasingly used in cancer care. Experts submit anonymized case reports to My Gene Counsel, and based on the details in these reports, Precision Oncology News writes a feature that describes the case history, challenges encountered by professionals in dealing with the case, and strategies they used in response to challenges or errors. The features also include a discussion with My Gene Counsel genetic counseling experts on better approaches that could be considered if similar cases are encountered in the future. In publishing this series, our aim is to educate experts in the field and foster discussion. If you would like to submit a case report, please email [email protected].

What happened?

A 49-year-old woman with a maternal family history of breast cancer was seen in a high-risk breast clinic. Both her mother and grandmother had breast cancer at an early age. Because her mother had reportedly declined genetic testing, the woman's Ob/Gyn had ordered testing the prior year and told her she was negative. The nurse practitioner at the high-risk breast clinic wanted to review the test results and requested a copy, only to learn that this woman did not have a "negative" test report. In fact, she had undergone testing on a multi-gene pan-cancer panel in 2018, which detected a pathogenic variant in one copy of the MUTYH gene.    

When individuals have a pathogenic variant in both copies of the MUTYH gene, they typically have MUTYH-associated polyposis (MAP), a hereditary cancer syndrome characterized by hundreds of colon polyps, and a 43 percent to 100 percent lifetime risk of colorectal cancer. Having one pathogenic MUTYH variant, as in this patient’s case, makes her a carrier of MAP. Around 1 percent to 2 percent of individuals of Northern European ancestry are MAP carriers, and some studies suggest their lifetime risk of colon cancer is modestly increased (between 7 percent and 13 percent), particularly when there is a family history of the disease

How was this case resolved?

The nurse practitioner informed the patient that her genetic test from 2018 had not been negative and that she actually harbored one copy of a pathogenic MUTYH variant. She recommended that the patient see a genetic counselor, and this referral is pending. Because the patient did not have a family history of colorectal cancer, her colon screening should not change at this time, based on current National Comprehensive Cancer Network guidelines. Her breast screening will be based on family history. 

Why is this case concerning? 

This patient got genetic testing because she had a family history of breast cancer. This case is concerning because while she may not have had any pathogenic variants, also known as mutations, in breast cancer risk genes that were tested, she was not "negative" for all the genes that were assessed by the multi-gene panel. It also appears that her doctor did not communicate the positive result she did have in MUTYH. "It’s hard to know if this was just an oversight or because the Ob/Gyn felt that [this finding] wasn’t important since it didn’t likely contribute to [the patient’s] family history of breast cancer and may not immediately affect medical management," said Meagan Farmer, who is a certified genetic counselor and genetic counseling business manager at My Gene Counsel.

She pointed out that guidelines change. In fact, if this test had been performed a few years earlier, the NCCN guidelines would have recommended colonoscopy at age 40 every five years for a person carrying one pathogenic MUTYH variant, even without a family history of colon cancer. "Although medical management wouldn’t be altered based on the patient’s reported family history and the current guidelines, that can change in the future based on new guidelines or if there is a diagnosis of colon cancer in a close relative," Farmer said.

From a genetics standpoint, since having one pathogenic MUTYH variant is relatively common, showing up in between 1 percent and 2 percent of some populations, this patient’s children or her siblings could have inherited two copies and have the more severe MAP condition. "This [result] is important to know about" for the patient’s relatives, Farmer noted.

With the increased availability of multi-gene panel tests that broadly gauge genes associated with risks for a variety of cancers, doctors may receive information that they didn’t expect. In this case, it seems that the provider may not have addressed positive test results outside of the patient’s reported family history of breast cancer. "It shows that providers are ordering these broader cancer panels even if they are interested in assessing a patient’s risk for a specific cancer," Farmer said. "If the provider is only interested in genetic test results that pertain to that patient’s clinical picture, perhaps they should consider ordering a targeted panel that only includes genes clearly associated with cancers in that family."  

What could have been done differently? 

This case highlights the importance of patients receiving all genetic test results, regardless of their medical picture.

After performing multi-gene panel testing for cancer risk, doctors may get back results that are "outside the box" in terms of the patient’s medical or family history. Anticipating this possibility, doctors should be more cognizant of the tests they’re ordering, Farmer said, and if they are ordering a broad, multi-gene panel, they need to have a plan for what to do in case of unexpected results. "And then, they have to be comfortable evolving that plan as guidelines continue to change," she added. "This provider didn’t give the result to the patient to begin with, much less come up with a plan."

Finally, patients should always request a copy of their genetic test report and carefully review the results, preferably with a certified genetic counselor when possible. This patient initially told the nurse at the high-risk breast clinic that her genetic test results were negative based on communication from her Ob/Gyn, without realizing that her doctor didn’t communicate to her all the test findings. "She didn’t realize she had this pathogenic MUTYH variant until she asked for a copy of her results," Farmer said.