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Genetic Testing Challenges in Oncology: Lynch Syndrome Variant in Patient Lacking Family History

Pregnant woman in one-on-one genetic counseling meeting

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 primary care doctor referred a 39-year-old Ashkenazi Jewish woman for genetic counseling because although she herself had never had cancer, some of her family members had, including her mother who had a pathogenic BRCA2 variant. However, the familial variant was not one of the three most common pathogenic variants in the BRCA1 and BRCA2 genes seen in individuals of Ashkenazi Jewish ancestry. The patient was also undergoing egg retrieval for in vitro fertilization and had told her doctor she would consider pre-implantation genetic testing of the resulting embryos if she had a high genetic risk for cancer.  

This patient had Ashkenazi Jewish ancestry on her maternal and paternal sides. Her mother, now deceased, had been diagnosed with breast cancer in her early 50s and had received full sequencing of the BRCA1 and BRCA2 genes, which revealed the BRCA2 variant. The patient also had a maternal grandfather who had lymphoma and melanoma, and a maternal grandmother with breast cancer in her 80s. Both maternal grandparents were deceased. The patient's father, who is still living, has never been diagnosed with cancer and knew of no relatives on his side with cancer.

How was this case solved?

After learning the patient's ancestry, her family's cancer history, and that there was a known familial variant, the genetic counselor suggested she get tested for the same BRCA2 variant her mother had and also for the three common BRCA1/2 variants prevalent in Ashkenazi Jewish populations to account for the Jewish ancestry on her paternal side. Additionally, since the patient was interested in pre-implantation genetic testing for any cancer-associated variants she might have, the genetic counselor discussed the possibility of casting a wider net for concerning variants using a multi-gene panel.

The patient agreed and had a panel test that assessed several genes associated with breast, gynecologic, and colon cancers. It turned out that she didn't have the familial BRCA2 variant present in her mother, but she did have a pathogenic variant in MSH6 that was a known founder mutation seen in high frequency among those of Ashkenazi Jewish ancestry. Pathogenic variants in MSH6 are associated with Lynch syndrome, an inherited condition that increases the risk of multiple cancers. Individuals with MSH6 pathogenic variants are estimated to have between a 10 percent and 44 percent lifetime risk of developing colorectal cancer, compared to around a 4 percent lifetime risk for the general population. MSH6 pathogenic variants are also associated with a heightened lifetime risk for endometrial, ovarian, kidney, and gastro-intestinal (GI) cancers.

The lineage of this particular MSH6 variant remains unclear, however, since by the time the patient underwent testing, her mother was deceased and additional testing wasn't possible to gauge if she harbored the MSH6 variant in addition to the BRCA2 variant. A paternal aunt did undergo genetic testing but was negative for the MSH6 variant. The patient's father hasn't yet been tested.

Since identification of the Lynch syndrome-associated variant, this patient has been seen by a GI doctor and a gynecologist/oncologist, and the patient has received a colonoscopy to screen for colon cancer and undergone an endoscopic procedure to screen for GI cancers, which were both normal.  

Why is this case concerning?

As seen with another case in this series (see here), this is an example of a patient harboring a pathogenic variant that doesn't align with what's known about her family history of disease. Multiple studies have shown that a germline genetic testing strategy heavily reliant on family history alone can fail to identify disease-associated variants in a substantial number of patients.

Furthermore, the case shows the complexity of ordering genetic testing, even when there is a familial variant. When a patient has a first-degree relative with a heritable pathogenic variant, it is standard practice to test first for that specific variant. But if the genetic counselor in this case had tested the patient for the BRCA2 variant her mother had and stopped there, and not considered other relevant factors, then the patient would not have learned she had an MSH6 Lynch syndrome variant.

"The genetic counselor showed really good judgment here," said Ellen Matloff, a certified genetic counselor and president and CEO of the digital health firm My Gene Counsel. "In addition to offering the patient testing for the familial BRCA mutation, the genetic counselor did something that made sense and also offered to test for the three BRCA1/2 Ashkenazi Jewish founder mutations based on her dad's Jewish ancestry. But then, they also discussed broader multi-gene panel testing, which would provide a more complete picture of this patient's genetic risk for cancer. This addressed the patient's needs of trying to keep herself healthy and, because she was undergoing IVF, her concerns about passing heritable mutations on to her child."

By considering the patient's ancestry and family history, as well as her goals for wanting genetic testing in the first place, the genetic counselor was able to offer the patient the appropriate array of testing options that ultimately revealed the pathogenic MSH6 variant she harbored. Given the history of racism in the field of genetics, some genetics experts have become more cautious about not conflating socially determined race with genetic ancestry in medicine and research, and may hesitate to ask patients, particularly people of color, about their ancestry, out of concern that it may be perceived as racist.

But in certain populations, like those with Ashkenazi Jewish heritage, discussing ancestry during the genetic counseling session may be critical to figuring out what test to order. "I would argue that ethnic background was very helpful here," Matloff said.

key takeaways_preimplantation genetic testing

What could have been done differently?

Fortunately, for this patient, the genetic counselor ordered the right tests based on her ancestry, family history of cancer, mother's variant, and personal motivations, and the strategy revealed a pathogenic variant associated with Lynch syndrome. While perhaps not much could have been done differently in this patient's case, but there are still outstanding questions that can present challenges for providers.

"We don't know where this patient's variant originated," Matloff pointed out. So far, a paternal aunt has tested negative for this variant, the mother cannot be further tested because she is deceased, and her father has not been tested. The patient's maternal and paternal grandparents lived until their late 70s and 80s and didn't have any MSH6-related cancers. None of her aunts on either side of the family have had cancer. This shows how difficult it can be to pin down a variant's lineage and more precisely understand the cancer risk within a family.

Lastly, and most importantly for Matloff, the reason this patient was undergoing genetic testing was because she is trying to have a baby through IVF and was concerned about having a heightened predisposition for cancer and passing down that genetic risk to her child. If she had a cancer risk variant, she wanted to test the embryos created through IVF for that same variant and would likely implant those that didn't have it.

The genetic counselor took this into account when managing this patient and discussed multi-gene testing as a way to look for a broader set of cancer-associated variants. But a recent Alabama Supreme Court ruling may make it harder for genetic counselors to discuss the full array of testing options with women undergoing IVF and considering preimplantation genetic testing. In February, Alabama's highest court ruled that embryos created through IVF are children and that fertility clinics could be held liable for wrongful death if they destroyed frozen embryos.

The ruling has far-reaching consequences, Matloff said, in that IVF clinics, fearing liability, may not be willing to do an egg retrieval and create embryos for patients who are at genetic risk for serious rare diseases and cancer. "Clinics may be reluctant to create embryos because they won't know what to do with the ones that carry a mutation," she said. "If five out of 10 embryos have the mutation and aren't implanted, then would the parents have to keep paying to keep those embryos frozen until the end of time? That really becomes a liability issue for the physicians, the IVF clinic, and the patient."

For genetic counselors working in Alabama or in other abortion-restrictive states considering similar restraints against fertility clinics, trying to provide patients appropriate care and present them with the full range of genetic testing options becomes an "incredibly nuanced problem," Matloff observed. "Can they counsel patients about these options like egg retrieval and IVF in a state like Alabama that considers an embryo from the very earliest stages to have the same rights as a human being? Could genetic counselors recommend patients go out of state, or would that to be breaking the law? It will really depend on the states and their interpretation of the law."