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Genetic Testing Challenges in Oncology: Full Family History Helps ID Lynch Syndrome Founder Variant

genetic counseling

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 35-year-old healthy man of Ashkenazi Jewish ancestry was referred for genetic counseling because his mother had a pathogenic MSH6 variant. Pathogenic variants in this tumor suppressor gene are associated with Lynch syndrome, an inherited condition known to significantly increase the risk of colorectal, prostate, pancreatic, ovarian, urinary tract, and other cancers. However, this patient's mother was in her 60s, had never had cancer, and hadn't undergone risk-reducing surgeries like oophorectomy or hysterectomy. However, the mother's brother had been diagnosed with pancreatic cancer in his early 60s, and her father had colon cancer in his 30s — both diagnoses consistent with Lynch syndrome.

At the genetic counseling session, the man was very anxious. After carefully reviewing cancer cases on both sides of his family, the genetic counselor uncovered that the patient also had a paternal grandmother diagnosed with pancreatic cancer in her 80s. The genetic counselor suggested the patient have testing for a panel of genes associated with pancreatic cancer since he had relatives with this type of cancer on both sides of his family and because he was of Ashkenazi Jewish descent, a group at heightened risk of certain cancers due to founder mutations.

How was this case solved?

The patient said he wasn't worried about the cancer history on his paternal side because his grandmother's pancreatic cancer diagnosis occurred at a late age. According to the genetic counselor, the patient "was adamant" that he did not want to undergo multi-gene panel testing to broadly assess his risk for hereditary cancer. The genetic counselor, however, was able to convince the patient to undergo full sequencing for MSH6, BRCA1, and BRCA2.

The test results showed that this patient did not have the pathogenic MSH6 variant found in his maternal relatives. However, he did have a different MSH6 pathogenic variant that is known to be a founder mutation in the Ashkenazi Jewish population. The genetic counselor recommended additional testing for this patient's father and confirmed that this variant was paternally inherited.

Based on this finding, the genetic counselor recommended that this 35-year-old patient receive guideline-backed screening for high-risk individuals, including colonoscopy every one to three years, esophagogastroduodenoscopy every two to four years, and annual urinalysis. The genetic counselor also advised the patient to promptly report any signs of neurologic cancers to his doctor, to consider pancreatic cancer screening starting at age 50, dermatologic screening every one to two years, and prostate cancer screening starting at age 40, and to discuss MSH6 testing with his reproductive partner.

Why is this case concerning?

This case is concerning because if the genetic counselor had ordered only single-site testing for the specific MSH6 pathogenic variant found in the mother, then the paternally inherited founder mutation would not have been detected.

In this series, the past few cases have highlighted the difficulties of managing patients after large gene panels uncover variants inconsistent with their families' cancer histories (see here and here). But this case deals with the opposite problem: the danger of testing a patient for too few genes when his family cancer history suggests the need for comprehensive assessment.

"This is how complicated the field of genetic testing is," said Ellen Matloff, a certified genetic counselor and president and CEO of the digital health firm My Gene Counsel. "It really takes an expert in genetics to decide what test to order and when and appropriately weigh for each patient the pros and cons of ordering a big panel versus single-site testing."

key takeaways_Ashkenazi founder mutation

What could have been done differently?

The case also highlights the importance of taking a complete family history and factoring in ancestry when determining which genes to assess. Given this patient had Ashkenazi Jewish ancestry, Matloff would have recommended testing BRCA1/2, just as the genetic counselor did, since cancer-associated founder mutations in these genes commonly occur in this population. "Whenever I saw patients of Jewish ancestry, and even if they were coming in for testing with a family history of a non-BRCA related cancer, I would always offer to test BRCA1/2, just based on how common founder mutations are [in this group]," she said. "It would be foolish to have them in for genetic counseling and not test those genes."

Ideally, Matloff would have also suggested this patient get tested for variants in all the hereditary cancer risk genes associated with pancreatic cancer, since it shows up on both sides of the family. The genetic counselor in this case also recommended broader multi-gene panel testing for this patient based on his full family history of cancer, but since he didn't seem to want this, Matloff was impressed that the genetic counselor was able to convince him to at least get full sequencing of MSH6 alongside BRCA1/2.

MSH6 pathogenic variants are linked with only around 7 percent to 10 percent of Lynch syndrome-associated cancers, whereas pathogenic variants in MSH2 and MLH1 are associated with 50 percent and up to 40 percent of cancers, respectively. If the patient had received testing for all the genes associated with pancreatic cancer, as was appropriate given this family's cancer history, then he would have been tested for variants in MSH6 along with several other genes, and he could have had a pathogenic finding in any one of them. The fact that the paternally inherited mutation turned out to be an Ashkenazi Jewish founder mutation in MSH6, "frankly, was a lucky find," Matloff said, but it underscores why taking a thorough family history on both sides of the family and considering ancestry is an important consideration when determining hereditary cancer risk.

In recent years, genomics researchers have spoken out about the need to move away from using socially determined race as a proxy for genetic ancestry in their work. But because race and ancestry are still often conflated in research and medicine, some genetic counselors have wondered whether it may be perceived as racist to ask patients, particularly people of color, their ancestry. And even if patients may know their ancestry, which isn't common, it may not be that informative for many patients in determining cancer risk or which genes to test for due to the lack of diversity in genomics research.

Matloff highlighted this case as an example of when knowledge of a patient's ethnic background can help genetic counselors navigate challenging interactions with patients and advocate for appropriate testing. "The genetic counselor in this case may not have pushed as hard for BRCA1/2 testing if she hadn't known that this man had an ethnic background where founder mutations in these genes are common," Matloff said. "And even with the known maternal MSH6 variant, testing revealed an Ashkenazi Jewish founder mutation in MSH6 instead, which shows that in certain cases, asking about ancestry can be clinically helpful."

It is unclear why this patient was focused on single-site testing, though concerns about high out-of-pocket costs associated with extensive work-ups can be a common worry for patients. Insurers can refuse to cover larger test panels and insist on single-site testing when there appears to be a familial mutation in the family, as it was in this case given the patient's mother had an identified MSH6 pathogenic variant. Since this patient had out-of-network insurance, the genetic counselor contacted the lab and confirmed that he would only be billed $100 for multi-gene testing. As such, lack of insurance coverage was not a barrier to broader genetic testing for this patient.