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, the 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 info@mygenecounsel.com.


What happened?

An oncologist began seeing a new patient – a woman who had previously had breast cancer, received genetic testing, and reported having a family history of cancer and Cowden syndrome. Based on this information, the oncologist referred her for genetic counseling.

The genetic counselor also went over her medical and family history and learned that she had been diagnosed with breast cancer at age 41. The patient recounted her family’s history of cancer and Cowden syndrome as outlined in the chart below:

The patient’s original treating physician had ordered multi-gene panel testing from a lab the genetic counselor was unfamiliar with. The genetic counselor reviewed the test report, which documented variants of unknown significance in the POLE and WRN genes. Cowden syndrome, caused by a pathogenic variant in the PTEN gene, increases the risk of breast, uterine, thyroid, colon, and kidney cancers, as well as melanoma. Often, Cowden syndrome patients have macrocephaly, or a large head circumference, non-cancerous tumor growths in the colon, and skin lesions. Patients may also be autistic and have intellectual disability. However, this patient’s head circumference was normal, and she said she didn’t have any of the characteristic skin lesions, though she said she hadn’t undergone a comprehensive dermatologic exam.

The patient’s test report did not indicate any findings in PTEN, and at the time of the appointment, she could not provide copies of test reports from relatives she said were PTEN positive. The genetic counselor told the patient that the test she received had not detected any pathogenic PTEN variants known to cause Cowden syndrome and that she didn’t have any other criteria that would suggest she had the condition. However, the patient was also unaware that she harbored VUS in two other genes, and the genetic counselor reviewed those results and their implications. Expert guidelines recommend against making clinical decisions based on VUS, and the patient’s personal cancer history was not consistent with what would be expected if she had a pathogenic variant in either of these genes.

The genetic counselor tried but could not obtain a copy of the test results from PTEN-positive relatives to confirm that they did indeed harbor a pathogenic variant. However, there was a genetic counseling letter for a maternal aunt that documented a pathogenic variant, an exon duplication in PTEN.

Since the genetic counselor was unfamiliar with the lab that tested the patient, she called and confirmed the lab was CLIA-certified and accredited by the College of American Pathologists. During the call, the counselor also asked a geneticist employed at the company if the lab could have detected the duplication reported in the maternal aunt. The geneticist said that the technological method employed by this lab could not have detected this type of variant.

How was this case resolved?

This meant that the lab may have missed the familial PTEN duplication in the patient, which concerned the genetic counselor. She tried again, unsuccessfully, to obtain a copy of a PTEN-positive family member’s test report. During this process, she learned that the patient’s mother had received genetic testing through a large commercial lab, which did not find a pathogenic variant in PTEN or other genes. The genetic counselor contacted this lab to make sure that it could have detected the reported familial variant. This was important to establish, since if the lab could have technically detected the duplication but did not identify it in the mother, then the genetic counselor could be more confident that the patient didn’t inherit this familial PTEN variant.

However, the lab needed permission from the mother and a copy of her report for review. The genetic counselor informed the patient of these requests.

Though this patient did not have many features often seen in Cowden syndrome, she still had a personal history of early-onset breast cancer and had gotten genetic testing through a lab that may not have robust methods of analysis. Now, the genetic counselor had concerns about whether the patient could have a pathogenic variant in another gene, which could explain her early breast cancer, but that the lab missed. 

At this point, the genetic counselor asked the patient to try again to obtain a copy of a PTEN-positive relative’s test report, to ask her mother to give permission to the lab to review her report, and to consider additional testing for herself to ensure she didn’t harbor pathogenic variants in other cancer risk genes that may have been missed. The genetic counselor further told the patient that as it stood, there wasn’t a genetic explanation for her early breast cancer, but that based on her personal and family cancer history, her daughters and other close female relatives should be followed closely. Her relatives could also consider genetic testing, but it would not be as informative without comprehensive genetic testing in the patient first.

The patient was surprised because she had assumed that her daughters were “in the clear” since genetic testing hadn’t detected any cancer risk variants in her. She said she would think about the genetic counselor’s requests but never followed up or returned the counselor’s calls. The genetic counselor sent a letter to the patient’s referring physician, who may have tried to follow up with her as well.

Why is this case concerning?

This case underscores the careful consideration that must go into determining the right genetic test for patients. It is concerning that the oncologist who ordered genetic testing for this patient did not do their due diligence in confirming that the lab could detect the familial PTEN variant. “The ordering physician didn’t realize that there is more to think about than if a gene is included in a panel,” said Meagan Farmer, a genetic counselor and genetic clinical operations director at My Gene Counsel. “There can be technical differences from lab to lab.”

Ideally, in this case, had it been possible to get ahold of a PTEN-positive relative’s report, Farmer would have tested this patient at the same lab as the relative. When testing a patient for a familial variant, she explained, it’s best to use the same lab that detected the variant in another family member. “We know that that lab can detect that family’s variant,” she said, adding that if a different lab must be used, then one should try to submit the test report from a positive relative and a sample as a positive control.

“Good labs will run the relative’s sample for free just to make sure they can detect the variant,” she said. “That way, if the patient tests negative, you can be more confident that it’s not that the lab couldn’t detect the familial variant but that the patient didn’t have it.”

It is also concerning that this family’s cancer history had been attributed to Cowden syndrome without checking the relevant documentation. Given how hard it was for the genetic counselor in this case to locate test reports of PTEN-positive relatives, it doesn’t appear that this patient’s doctors actually tried to confirm that a pathogenic variant in PTEN was actually causing cancers in this family.

“We don’t know that all those cancers reported in the family are due to a pathogenic PTEN variant,” Farmer said, emphasizing that there remains a concern in this case that the lab the patient received testing through may have missed cancer-associated variants in other genes due to its technical limitations.

What could have been done differently?

The ordering provider should have carefully reviewed the familial variant in this family and, ideally, ordered testing from the same lab that had detected the PTEN variant in the maternal aunt or a lab that could detect that variant. “At least, the oncologist should have made sure that the lab conducted comprehensive deletion and duplication analysis since the reported familial mutation was a duplication,” Farmer said.

But even if this is not possible, the close female relatives of a woman who has had breast cancer in her 40s and has a strong family history of breast and gynecologic cancers, are at heightened risk of cancer and should receive further counseling and screening just based on that information. “If you do all this genetic testing in a woman in her early 40s with breast cancer, and no pathogenic variant is detected, we still need to make screening recommendations for her and her family based on this history,” Farmer said. “An uninformative genetic test result doesn’t mean they are in the clear.”

Written by Turna Ray. Genetic counseling discussion provided by Meagan Farmer, MS, CGC, MBA. Originally published on PrecisionOncologyNews.com.