Genetic Testing Results: How to Interpret Your Report

Receiving your cancer genetic testing results can be both enlightening and overwhelming. These reports contain valuable information about your genetic makeup that could impact your health and your family members. Understanding these results is crucial for making informed healthcare decisions, especially regarding cancer risk assessment. Remember, genetic counseling is there to provide support and guidance, making this journey less daunting.

In this guide, we'll break down the three types of genetic testing results you might receive when you undergo hereditary cancer testing—positive, negative, and variants of uncertain significance—and explain what each means for your cancer risk and follow-up care.

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Understanding the Basics of Genetic Testing

Before diving into results interpretation, it's important to remember that genetic testing looks for specific changes (mutations) in your DNA that may increase your risk of developing certain types of cancer. These tests analyze genes that play crucial roles in cellular functions like DNA repair, cell growth, and tumor suppression.

The type of genetic test you undergo depends on your personal and family history. For the purposes of this article, we will be referring to testing using panels of multiple genes related to certain cancer types.

Now, let's explore what different test results mean for you.

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Positive Results: When a Mutation Is Found

A positive result means the laboratory has identified a pathogenic (disease-causing) or likely pathogenic mutation in one or more of the tested genes. This mutation is known to increase the risk of developing specific types of cancer.

What Does a Positive Result Mean for Your Cancer Risk?

When you receive a positive result, it's essential to understand that this doesn't mean you will develop cancer. Instead, it indicates an increased risk compared to the general population.

For example, a woman with a BRCA1 mutation has approximately a 60-80% lifetime risk of developing breast cancer and a 40-60% risk of ovarian cancer, compared to the general population risks of about 12% for breast cancer and 1-2% for ovarian cancer.

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Understanding DNA Repair Genes and Cancer Risk

Many hereditary cancer syndromes involve mutations in DNA repair genes. 

To understand why these mutations increase cancer risk, it helps to know how some of the genes tested usually function:

1. DNA Repair Mechanism: Your cells are constantly repairing DNA damage caused by environmental factors and normal cellular processes. Specific genes produce proteins that identify and fix this damage.

1. The Knudson "Two-Hit" Hypothesis: One regular copy is enough for many cancer-predisposing genes to maintain proper function. You still have one functioning copy when you inherit a mutation (the first "hit"). However, if the remaining good copy acquires a mutation during your lifetime (the second "hit"), the repair function is lost in that cell, potentially leading to cancer development.

1. Accumulated Damage: When DNA repair genes don't function properly, damage accumulates more rapidly, increasing the likelihood of cells becoming cancerous.

This explains why people with inherited mutations in DNA repair genes like BRCA1, BRCA2, MSH2, MLH1, and others have higher cancer risks and often develop cancer at younger ages than the general population.

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Next Steps After a Positive Result

If you receive a positive result, your healthcare provider will likely recommend:

• Enhanced screening protocols starting at younger ages
• Risk-reducing medications or surgeries that may be appropriate
• Testing for family members who may share the same genetic risk
• Lifestyle modifications that may help reduce cancer risk

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Negative Results: When No Mutation Is Found

A negative result means the laboratory did not identify any known pathogenic mutations in the tested genes. However, it's essential to understand what a negative result does and doesn't tell you.

What a Negative Result Doesn't Mean

A negative result doesn't guarantee that you won't develop cancer. It simply means that you don't have have mutations in the specific genes that were tested. 

You may still have:

• Mutations in genes that weren't included in your test
• Mutations that current technology cannot detect
• Other risk factors for cancer, including environmental exposures, familial risks or lifestyle factors

Additionally, with a negative result, risk still must be estimated based on family history. 

Interpreting Negative Results in Context

The significance of a negative result depends heavily on your personal and family history:

• Strong Family History: If you have a significant family history of cancer but test negative, your doctor might still recommend enhanced screening based on that history. As an example, risk calculators like the Tyrer-Cuzick model can help assess breast cancer risk based on family history and other factors.
• No Family History: If you don't have a concerning family history and test negative, your cancer risk is likely similar to the general population's.
• Known Family Mutation: If a specific mutation has been identified in your family and you test negative for that particular mutation, your risk is generally considered the same as the general population's risk.

Next Steps After a Negative Result

Even with a negative result, your doctor may recommend:

• Standard or enhanced cancer screening based on your age, family history and other risk factors
• Continued monitoring of your family history
• Healthy lifestyle choices to reduce general cancer risk

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Variants of Uncertain Significance (VUS): The Gray Area

What can be the most challenging result to interpret is a variant of uncertain significance (VUS). This means that a change in the DNA was found, but there isn't enough scientific evidence to determine whether this variant increases cancer risk.

Categories of Variants

Genetic variants are generally classified into five categories:

1. Pathogenic: Known to increase disease risk. We would consider this a “positive” result
2. Likely Pathogenic: Probably increases disease risk, but less certain
3. Variant of Uncertain Significance (VUS): Insufficient evidence to classify as harmful or harmless
4. Likely Benign: Probably doesn't increase disease risk. 
5. Benign: Known not to increase disease risk. We would consider this a “negative” result

A VUS falls in the middle of this spectrum—any variant where there is lack of clarity as to whether it is harmful, is considered a variant of uncertain significance.  

Why Variants May Be Uncertain

A variant might be classified as a VUS for several reasons:

• It's a newly discovered variant with little available research
• Studies show conflicting evidence about its effects
• It's rare in the general population, so there's limited data on its impact
• The change occurs in a portion of the gene whose function isn't yet well understood

What Happens to VUS Classifications Over Time

As researchers gather more data, many VUS are eventually reclassified. Most variants of uncertain significance are ultimately determined to be benign. 

This reclassification process depends on:

• Population studies tracking the variant in affected and unaffected individuals
• Functional studies examining how the variant affects protein function
• Family studies observing whether the variant tracks with the disease in families
• Data sharing between laboratories through resources like ClinVar, a public database that aggregates information about genetic variants

Managing Cancer Risk with a VUS Result

When a VUS is identified, healthcare providers typically:

• Will not make treatment decisions based solely on the VUS
• Consider your personal and family history to guide screening recommendations
• May suggest periodic check-ins to see if the variant has been reclassified
• Might recommend testing other family members to gather more information

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The Importance of Genetic Counseling

Regardless of your test result, working with a genetic counselor is invaluable for:

• Understanding the full implications and limitations inherent to your results
• Determining appropriate next steps for you and your family
• Addressing emotional and psychological concerns
• Navigating insurance coverage and privacy issues
• Staying informed about reclassifications or new testing options

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Conclusion

Genetic testing results provide robust information that can help guide your healthcare decisions but require extremely careful interpretation. Remember that these results are just one piece of your overall health picture. Your personal medical history, family history, and lifestyle factors all contribute to your cancer risk.

By understanding what your genetic testing results mean—and what they don't mean—you can make more informed decisions about your health and potentially reduce your risk of developing cancer or detecting it at an earlier, more treatable stage.

If you have undergone genetic testing or are considering it, we encourage you to discuss your results or questions with a genetic counselor who can provide personalized guidance based on your unique situation. Visit us online at https://www.jscreen.org/ to learn more.