Interpreting Results for Hereditary Cancer Genetic Testing

Interpreting Hereditary Test ResultsIncreasingly, providers use multi-gene panels as a first-tier test as opposed to testing a single gene or testing multiple genes in a stepwise manner. There are many different kinds of panels available, large and small, cancer-specific (e.g., breast cancer, gastrointestinal cancer) and pan-cancer, and variability is seen even within similar tests offered by different laboratories. These expanding options can present challenges when applying test results to patient management.

"Often, providers are not sure if they are looking at a positive result or a VUS, a variant of uncertain clinical significance. When they are unsure, they’ll most commonly say it is a positive result but, when Sherry accesses the report, it turns out to be a VUS."

We spoke with Sherry Boyar, a genetic counselor and clinical science liaison (CSL) at Invitae to find out the most frequent questions providers ask when faced with interpreting test results. Sherry, with her long history in cancer genetic counseling, views her role as a CSL through a clinical lens, and often works with providers to give them the information they need to communicate effectively with their patients.

Here are 5 of the most common questions Sherry gets from providers about interpreting genetic test results.

1. I don't know what this result means- what is this?

Often, the provider’s first question is about the result in general, to check their own understanding. Hereditary cancer test reports are dense with information and can be difficult to read. Usually, the questions Sherry gets are about facts already contained in test results; providers contact her because they have a strong sense of responsibility in interpreting it right. The primary concern is that they may not have the expertise to help their patient. Often times, a patient may be sitting in the exam room, heightening the urgency of their call.

For some providers, the reason they reach out is because they have a genuine desire to become more fluent in what they are looking at and better versed in explaining things.

2. What are the implications of a positive result in this particular gene?

Even though many providers Sherry speaks with have experience using genetics in practice (e.g., BRCA1), they often have questions about the implications of finding a variant in less familiar genes (e.g., CHEK2). These providers are looking for guidance because they have not had a conversation with a patient about a positive result in these genes before. Increasingly, Sherry will be able to tell the provider that the gene is well-described in the literature now, and will point them towards management guidelines, if available. For those genes with less information available, her message is, “Our understanding of the scope of cancer risk is really a work in progress. There may be a number of cancer risks which aren’t clear yet.” She spoke of a recent case with a CHEK2 pathogenic variant and a broad spectrum of cancer history in that family. For the thyroid cancer in the family, she told the provider that it has been described in CHEK2 but the actual empiric risk for other family members isn’t clear. Making a connection with genetic services can help providers feel supported in their practice.

3. What does this specific variant mean?

Often, providers are not sure if they are looking at a positive result or a VUS, a variant of uncertain clinical significance. When they are unsure, they’ll most commonly say it is a positive result but, when Sherry accesses the report, it turns out to be a VUS. She also helps clarify the understanding of what a VUS actually is.

4. I get that the variant has uncertain significance, but it is in a suspicious gene – doesn’t that mean something?

With a VUS, she will explain that we are looking at something without sufficient data to characterize it as either positive or negative. She advises the provider to explain to the patient that it is not something we act upon clinically. Some understand this, but still may be missing the point that we are back to approaching the patient as if the result were negative. She will advise them that it is still important to be responsive to the personal risk factors and family history, which may increase a patient’s risk for cancer.

Because providers are concerned about clinical impact, a VUS result can be difficult. In this era of panel testing, especially with large panels, providers may feel like the result is meaningful because the VUS is in a gene that matches the patient’s personal and family history. For example, when there is a family with multiple relatives diagnosed with uterine cancer and a MSH6 VUS is detected (MSH6 is one of the Lynch syndrome genes and increases the risk of colorectal and uterine cancer, among others), the provider begins to feel uncomfortable with the interpretation that the variant is of unknown significance.

The provider may have a different perceived possibility: that the variant is coming up in a lottery kind of way: “What is the chance that a variant came up in only this one gene, the one of most interest, when we looked at 47 or 83 genes?” Sherry will acknowledge that it does feel uncomfortable, anybody would understand it feels uncomfortable, but having researched this particular variant, she doesn’t see any compelling reason to treat it differently. She will be sure to advise them that they can’t look at the VUS as the answer for the patient and/or the family.

5. I tested somebody at high risk who has a negative result. What do I do now?

Negative results, while for some can be very reassuring regarding future cancer risks, can be concerning for others. Specifically, when the patient’s personal and/or family history is concerning for a hereditary syndrome, not finding a pathogenic variant can be disconcerting for the provider.

A negative result on genetic testing can indicate that the patient does not carry the variant causing cancer in the family. This result is most reliable when the patient tests negative for a known pathogenic variant in the family. When that patient has a concerning history (for example, early DCIS with a known BRCA2 pathogenic variant in her sister) it seems inconceivable their patient does not have the pathogenic variant that her younger sister has. She’ll hear, “That’s impossible!” or, “How could that be?” Sherry will explain that this is actually quite common, and it is plausible this cancer was sporadic within a positive family. Sometimes there is actually more than one pathogenic variant in a family, so this possibility should be assessed.

When a pathogenic variant has not been previously identified, a negative result can be difficult to interpret. In these cases, Sherry explains that “sometimes a negative result can be uninformative.” There is the possibility that there is a hereditary cancer syndrome in the family that the patient did not inherit. It may be that the patient carries a pathogenic variant in a gene or region of a gene that was not analyzed, due to limits of today’s technology (e.g., detecting deep intronic variants) or it not being present on the panel testing. While the risk for lab error or sample mix up is low, this question should be explored when the pre-test suspicion for a positive result is unusually high.

When the negative result is uninformative, next steps may involve further testing and/or consideration of referring to a genetic expert. In considering further testing, if the patient tested was unaffected, Sherry will help the provider identify which relatives would be informative, and how to discuss pursuing testing of these relatives with the patient.

In all cases, Sherry will look at the complete family history and assess the tests previously ordered. If additional testing to further investigate a genetic cause makes sense, she will help re-requisition the case, allowing for further testing without the need to submit a new sample. Sherry notes that she has seen more than one mutation in a family, which additional testing may detect.

Providers do not have as much appreciation for next steps, such as treating their patient as positive when they meet clinical diagnostic criteria for a hereditary syndrome, even when they have negative genetic test results. This is an important consideration that can make a difference in management of their patients.


Sherry says she is glad when clinicians call with questions about interpreting results, because it provides the opportunity to help them care for their patients in the best way possible.

Often, the provider is not sure where to go for more genomics education. They understand the preventive value of genetic risk assessment and testing, and are really committed to reducing the risk of a future cancer. This is extremely exciting to Sherry. She wants to make helping them develop these skills a greater part of her own practice. A message she often hears is, “If I can do something to prevent cancer or save lives, through a blood test, that is very empowering.” And, she adds, that is exactly how everyone in the profession feels.