Genetic testing can decrease but not rule out cancer risk

Breast cancer risk assessment is increasingly included in primary care. As a rule of thumb, approximately 5-10% of individuals with a breast cancer diagnosis will be found to carry a pathogenic variant (mutation). This means that in the majority of cases, a pathogenic variant will not be identified. When faced with a negative genetic testing result, what you do next to manage a patient’s cancer risk varies depending on what her risk was before the test.

Let’s consider two patients, Sonia and Jane. These two women appear to be similar, at first. They are both 35 years old, have not had a personal diagnosis of cancer, and maintain a healthy weight and lifestyle. Sonia’s family history includes her mother’s ovarian cancer diagnosis at 70 and a maternal aunt with breast cancer at 75. Jane’s family history includes breast cancer for her mother at age 55, maternal grandmother at age 60 and a maternal aunt at 40.

Genetic testing used a nine-gene panel assessing primarily breast cancer susceptibility genes. Results were negative for both Sonia and Jane.

Fine tuning your risk assessment after negative result

Both women can be relieved with a negative result, right? Not so fast. Genetic testing decreases but does not rule out risk. This has little to do with to do with analytic validity. Commercial labs doing clinical hereditary testing are CLIA- and CAP- certified, and their processes for gene sequencing and rearrangement analysis are very accurate. Instead, consider what was tested. The panel included the likely culprits – nine genes known to contribute to the risk of developing breast cancers. But those nine genes are not the only ones that may be associated with breast cancer risk; they are just the ones that are the most common that convey the greatest risk. It is possible Sonia or Jane could carry risk variants not analyzed in the test. And, even within these nine genes, there could be certain variants that cannot be detected with the technologies used. For these reasons, a negative result does not have the same meaning for every patient.

So how do you fine-tune your risk assessment? Next steps are to review what has already been done (re-examination of the test performed and the family history) and determine your patient’s residual risk of breast cancer.

Review the test report to determine if the test included the appropriate genes. In Sonia’s case, her mother had ovarian cancer. The nine-panel test would have ruled out hereditary breast and ovarian cancer syndrome, as BRCA1/2 would have been tested. It may not have ruled out other genetic risks for ovarian cancer. While the link to breast cancer is generally recognized among clinicians, the association of ovarian cancer to other syndromes, such as Lynch syndrome, may not be as well known. There are also some genes known to increase the risk of ovarian cancer alone, and these genes may not have been included in the test. Some labs will reanalyze their data within a short time frame if you realize some genes of interest were not included in the original report.

Test an affected relative. Is there a relative whose test may be more informative? If any relatives who had breast or ovarian cancer are living, their genetic test results could help clarify those for Sonia or Jane. For example, if Jane’s mother were found to carry a pathogenic variant (mutation) in a gene included on nine-gene panel, Jane would be considered a “true negative,” and at general population risk for breast cancer. Have a conversation about how genetic evaluation for those relatives, and possible genetic testing, would help them understand the importance for themselves and their families.

Perform a risk assessment. Even as you pursue the steps above, you can estimate whether a patient has a risk of breast cancer that is higher than in the general population. The Tyrer Cuzick, BRCAPro and other models weigh personal and familial factors, and can help refine a woman’s 5-year and lifetime breast cancer risk.

Each model’s algorithms weights these factors differently, but if 5-year risk is 1.66% or more, a woman may consider chemoprevention, such as taking Tamoxifen. If lifetime risk is 20% or higher, she may consider more intensive screening, such as earlier mammography and breast MRI.

Based on her age, healthy weight, reproductive and family history, Sonia’s risk assessment using BRCAPro and other models show that her 5-year risk is not increased. She is estimated, after negative testing, to have 16% lifetime risk of developing breast cancer using the Tyrer Cuzick model. This is only slightly increased over the average woman’s risk of 12.5%. On the other hand, Jane, whose personal risk factors are similar to Sonia’s, has a 5-year risk of 1.2% but her lifetime risk is 29%. Jane can be referred to genetic services or a high risk breast clinic to get support in making decisions about what preventive measures may be right for her.

Re-evaluate over time. Keep in mind that risk factors may change over time. You’ll want to be sure to update Sonia and Jane’s personal and family history at annual visits and re-evaluate risk and management recommendations as appropriate.


Your patient’s baseline risk matters for interpretation of cancer genetic test results. Even though a negative hereditary cancer genetic test can rule out some or most of the risk, family history and personal factors may still contribute to an increase in risk and patients should be followed appropriately.

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