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Genetic Testing Challenges in Oncology: Confusion Over Colon Cancer Syndromes Leads to Wrong Testing

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?

During a visit with a new primary care physician, a 45-year-old man told his doctor that he had a family history of cancer and Lynch syndrome, a hereditary condition that increases the risk for colon, uterine, and other cancers. He also recounted that he had tested negative for Lynch syndrome in 2013, and as a result, he had stopped having colonoscopy screening since it seemed he didn't have a familial condition and he hadn't reached the age for colon cancer screening for the general population.

The physician referred him to a genetic counselor to ensure he would receive the appropriate follow-up care. The counselor reviewed the patient's medical and family history, including prior genetic testing records. The patient's records showed a family history of various cancers. The patient's maternal grandmother was diagnosed at age 50 with breast cancer; his paternal grandfather had prostate cancer in his 60s; and his sister, father, and paternal aunt were reported to have had Lynch syndrome.

His records also showed that seven years ago he was tested for mutations in four genes associated with Lynch Syndrome — MLH1, MSH2, MSH6, and PMS2 — and was negative. (At the time EPCAM was not routinely tested as part of Lynch syndrome assessment but is now.)

In order to confirm the patient's verbal account of cancer risk in his family, the genetic counselor requested to see his sister's genetic test report. The patient called his sister during the visit, and she located her results and read it over the phone. She said she had a pathogenic variant in the APC gene, which is associated with familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) — an entirely different hereditary cancer syndrome — not Lynch syndrome. The genetic counselor asked the sister additional details about her case over the phone and asked her to send in the genetic test report to confirm that her test result and medical history were most consistent with AFAP.

How was this case resolved?

The genetic counselor informed the patient that he had not received the right genetic test to determine if he also harbored the genetic risk for AFAP. The patient decided to receive targeted testing for the specific APC variant that his sister has. He was negative. Though the patient was relieved at the outcome, he was also angry at his gastroenterologist for ordering the wrong test in 2013 and was considering suing him.

Why is this case concerning?

Patients with Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, often have mismatch repair deficiency or microsatellite instability, which leads them to develop colorectal, uterine, and other gastrointestinal cancers at a young age, usually before 50. APC-associated polyposis conditions, such as FAP and AFAP, are also known to increase the risk of colon cancer in families though the risk is much higher than it is with Lynch syndrome, and cancer can manifest at an even younger age.

People with FAP develop hundreds to thousands of colon polyps and have nearly 100 percent risk of developing colorectal cancer without a preventive colectomy. AFAP is less severe, where patients develop 10 to 100 polyps and have a 70 percent lifetime risk for colon cancer without appropriate screening, and preventive colectomy, if needed. Patients who are APC mutation-positive are recommended to undergo colonoscopy every one to two years.

"With Lynch syndrome you do see colon cancer, but unlike FAP and AFAP, you don't see significant polyposis," said Meagan Farmer, who is a certified genetic counselor and genetic counseling business manager at My Gene Counsel. "These conditions typically look clinically different and are caused by pathogenic variants in different genes. However, it could be more challenging to distinguish the two clinically if someone with AFAP has a relatively low number of polyps."

To Farmer this case demonstrates how failure to diagnose the right condition and order appropriate genetic testing puts patients and their family members at risk, and wastes healthcare dollars.


The negative Lynch syndrome test essentially provided false reassurance to this patient about his colon cancer risk, she said. If this patient turned out to be APC mutation-positive, it could have been a missed opportunity for cancer prevention or early detection for not just the patient but his at-risk relatives. Farmer pointed out that testing of children of patients who have AFAP should strongly be considered, since each child has a 50 percent chance of harboring the same variant.

"This put multiple people at risk," Farmer said. "You can understand why this patient was so angry and was considering suing his doctor."

Although genetic testing costs are coming down, this type of testing is not cheap. At the time the patient was tested for mutations in the four Lynch syndrome genes, such assessment could cost upwards of $4,000. Single-site testing for the APC variant that the patient's sister had is what should have been ordered, which would have been between $400 and $500. "It's not just that the wrong test was ordered, a much more expensive and wrong test was ordered," Farmer said.

What could have been done differently?

Although the patient was initially tested for Lynch syndrome, the familial condition he should have been tested for was AFAP. Moreover, it was noted throughout this patient's medical record that he had a family history of Lynch syndrome.

Although the two conditions are different and involve completely different genes, Farmer has seen healthcare providers mix up the two conditions before. "If you were to think of hereditary conditions linked with colon cancer, and asked anyone who knew something about this to name a couple, they'd name Lynch and FAP," she said, adding that if doctors are unsure which genetic condition to test for, they should refer their patients to a genetic counselor.

However, it isn't clear from the information available on this case how the confusion happened. Did the gastroenterologist conflate the two conditions when diagnosing the patient? Did the patient tell the doctor the wrong condition and it got entered in the medical record as him having a family history of Lynch syndrome?

Regardless, the mistake could have been avoided had the doctor confirmed that the patient actually had a familial risk for Lynch syndrome and requested access to the sister's test report, as the genetic counselor eventually did. "Instead of looking at a test result and verifying that, it just got put in the medical record, and then everyone who saw him said, 'Oh, yeah, you have a family history of Lynch syndrome,'" Farmer said. "And then, the wrong test was ordered."    

As a genetic counselor, she never makes conclusions about a patient's condition or disease risks just based on a verbal account of family history. Farmer tries to procure evidence that a genetic condition truly exists in the family by getting a hold of relatives' genetic test results. If this information isn't available, then she "starts from scratch" and develops a testing strategy based on the constellation of cancers in the family and other clinical signs, such as if relatives had colon polyps.