What Cascade Testing Actually Means (and Why It Matters for Your Family)

By Amanda Shrewsbury, MS, CGC

When a person in a family tests positive for a mutation related to hereditary cancer risk, after initial recommendations are made, conversation then shifts to the family, beginning the process called cascade testing.

This conversation can feel heavy. Someone has just received information that changes their own medical care, and almost immediately they are asked to think about parents, siblings, children, aunts, uncles, and sometimes farther-out relatives. The good news is that cascade testing is one of the most efficient and well-established processes in hereditary cancer care, and a genetic counseling conversation makes sure each family member gets the right testing approach for their specific situation.

This post is for anyone who has just learned a family member tested positive and is wondering what to do next, anyone who has tested positive and is preparing to talk with family, and anyone who simply wants to understand how cascade testing works.

What is cascade testing?

Cascade testing is targeted genetic testing of family members for a specific pathogenic variant that has already been identified in one relative. It is sometimes called known familial variant testing, which is the term you may see on a lab order form or in a clinical note. Both terms describe the same idea: once a specific variant has been identified in a family, relatives can be tested for that exact variant.

This is a different process from the initial genetic testing that identified the variant in the first place. The first person tested (often called the proband) usually has a multi-gene panel run, which looks at many genes at once to figure out what is going on in the family. Once a variant has been identified, family members can be offered a specific test that looks only for that exact variant.

Why does cascade testing matter for families?

When a pathogenic variant is identified in one person, first-degree relatives (parents, siblings, and children) have a 50 percent chance of carrying the same variant. Cascade testing turns that probability into clear information.

For people who test positive, the result opens the door to earlier and more intensive cancer screening, opportunities for risk-reducing interventions, and informed reproductive decision-making. For people who test negative, the result can mean a return to general-population cancer risk for the gene in question, which is often a meaningful reassurance and reduces unnecessary screening.

The decisions that come out of cascade testing are some of the most actionable in all of cancer prevention. Knowing who in a family is affected and who is not can change the trajectory of cancer care for an entire generation.

Who should consider cascade testing?

First-degree relatives are typically the starting point. From there, depending on who tests positive, the cascade can move outward to second-degree relatives (aunts, uncles, grandparents, nieces, nephews, and half-siblings) and beyond. The pattern is "cascading" because each new positive result identifies additional first-degree relatives who may then be candidates for testing.

The specific decisions about who in a family should test, in what order, and what type of test to use are not automatic. They depend on the family structure, the ages of relatives, the specific gene involved, and other factors that come up in a genetic counseling conversation. A genetic counselor can help map out the family and recommend a sensible path through it.

Should I do single-site testing or a multi-gene panel?

This is one of the most important questions in cascade testing, and the answer is not always obvious.

When a family has a known pathogenic variant, the most efficient cascade approach is usually single-site testing, which looks only for the specific variant identified in the family. Single-site testing is faster, less expensive, and more straightforward to interpret than a full panel. For some people, it is the right choice.

But there is an important exception. Research from large hereditary cancer testing populations has shown that approximately 1 to 4 percent of people who test positive for one pathogenic variant turn out to carry a second pathogenic variant in a different gene (Neumann et al., 2025). When that second variant exists, single-site testing for only the first variant will miss it.

A concrete example helps. Imagine a person whose mother carries a pathogenic MLH1 variant (one of the Lynch syndrome genes). The standard cascade approach would be single-site testing for that specific MLH1 variant. But what if this same person's paternal family history includes multiple cases of breast and ovarian cancer? In that situation, the paternal family history points towards a possible second mutation explaining it, and a multi-gene panel would be the better choice. The panel would still identify the maternal MLH1 variant if it is present, and it would also screen for variants in BRCA1, BRCA2, and other genes that the paternal family history raises questions about.

This is the single most important reason that a genetic counseling conversation matters before cascade testing, even when the family already has a known variant. A genetic counselor reviews the full family history on both sides, considers the specific genes involved, and helps decide whether single-site testing or a multi-gene panel is the right approach for that particular family member. Without that conversation, important findings can be missed.

How does cascade testing work, step by step?

The process is usually straightforward once the testing plan is in place.

  • The proband's genetic test report is the starting point. The specific variant, the gene, and the lab that identified the variant are all documented and become the reference point for cascade testing.
  • Family members meet with a genetic counselor to discuss testing. This is where the single-site versus multi-gene panel decision happens, based on the full family history.
  • The test is ordered. Most commercial laboratories offer known familial variant testing as a separate, lower-cost test option when there is documentation of the variant in a relative.
  • Results return. Single-site testing typically returns more quickly than a full multi-gene panel.
  • A genetic counseling appointment to return the results and discuss next steps. What happens after depends on the result and the gene involved, but the conversation typically covers screening recommendations, risk-reducing options if applicable, and implications for other family members.

Does insurance cover cascade testing?

In most cases, yes. When there is a documented pathogenic variant in a first-degree relative, insurance coverage for cascade testing is typically more straightforward than coverage for initial diagnostic testing, because the proband's positive result establishes medical necessity for testing family members.

For people without insurance coverage, self-pay options through commercial laboratories may be more affordable for known familial variant testing than for full multi-gene panels, given the narrower scope of the test. A genetic counselor can help walk through what the costs are likely to look like for a specific situation. Our post on insurance and the cost of genetic testing covers this in more detail.

What if I test negative when a family member tested positive?

A negative result on a properly designed cascade test is meaningful information. When a person tests negative for the specific variant identified in their family, this is sometimes called a true negative result. It means the person did not inherit the variant that is in their family, and risk for cancers associated with that genetic mutation likely return to general population levels.

This is a real and important kind of reassurance. The screening and management recommendations that applied to the affected relative do not apply to the person who tested negative for the family's variant.

That said, a true negative does not mean zero cancer risk. General-population cancer risk still exists, and a negative cascade test does not address risk from any genes that were not tested. Additionally, screening recommendations are still made based on family history, such as undergoing increased and possibly earlier screening due to family history of breast cancer. This is another reason the single-site versus multi-gene panel decision matters: if there is family history on the other side of the family that the cascade test did not address, that history still warrants its own conversation.

How do I tell family members about a positive result?

This is one of the most common questions people ask after receiving a positive genetic test result, and there are no universal rules. The decision to share, the timing, and the approach are personal. Some families have open conversations about health; others have long-standing patterns of privacy that make this kind of disclosure complicated.

Genetic counselors often provide what is called a family letter, a document that summarizes the genetic finding in non-technical language, explains what the variant means for relatives, and provides information that family members can bring to their own clinicians. A family letter takes some of the burden off the proband and gives relatives something concrete to work with.

Our post on talking to family about genetic testing goes deeper into the practical and emotional pieces of this conversation, including suggestions for different family dynamics.

What if family members are estranged, or there is no contact?

Family estrangement, lost contact, deceased relatives, and complicated family dynamics are all common realities in cascade testing conversations. A genetic counselor can help work through what is possible given the family situation.

The goal of cascade testing is to share information with the family members who can receive and act on it, while recognizing that not every family is built to do that fully.

What should you do next?

If a family member has tested positive for a hereditary cancer variant, or if you yourself have tested positive and are thinking about how to share with relatives, the most useful first step is a genetic counseling appointment. A genetic counselor can review your situation, recommend the right type of testing for you (single-site or multi-gene panel), help you think through the family conversation, and provide a family letter if that would be useful.

A few additional resources from our blog that may help:

Why this matters

Cascade testing is one of the most important aspects of hereditary cancer care, as it can identify other family members who are at-risk and can potentially be life-saving.

---

References

Facing Our Risk of Cancer Empowered (FORCE). (2025). Cascade testing and known familial variant testing. https://www.facingourrisk.org/

National Comprehensive Cancer Network. (2025). NCCN clinical practice guidelines in oncology: Genetic/familial high-risk assessment — Breast, ovarian, and pancreatic. https://www.nccn.org/

Neumann, C., Dedousis, D., & Hall, M. J. (2025). Risks and implications of multiple actionable pathogenic germline variants discovered by panel-based cancer predisposition testing. JCO Precision Oncology, 9, e2400951.

---

This blog post is for educational purposes only and does not constitute medical advice, diagnosis, or treatment. Always seek the advice of your physician, genetic counselor, or other qualified healthcare provider with any questions you may have regarding a medical condition or your individual health needs.