Podcast Summary
Podcast Summary for S2E7: What Does “Variant of Uncertain Significance” on a Genetic Report Actually Mean? How Genetic Counselling Supports You?
Yoyo Chu
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Full episode is available here (in Catonese).
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What Is a VUS? Understanding Variants of Uncertain Significance
A VUS (Variant of Uncertain Significance) is a genetic variant identified in a genetic test report that falls into the third tier of the international five-tier classification system — sitting squarely in the grey zone between “benign” and “pathogenic.”
International clinical genetics standards classify genetic variants into five categories: benign, likely benign, uncertain significance (VUS), likely pathogenic, and pathogenic. A VUS sits at the centre of this spectrum, where existing scientific evidence is insufficient to confirm harm or to rule it out.
A VUS is not a sign that genetic testing has failed. Rather, it reflects science choosing responsible humility in the face of biological complexity — opting to say “we don’t know yet” rather than offering a potentially incorrect conclusion with serious consequences.
When evaluating whether a genetic variant has clinical significance, scientists consider a range of factors: how frequently the variant appears in healthy populations, whether it is repeatedly documented in affected individuals, its predicted impact on protein function from a biochemical standpoint, and whether functional studies or animal models support a harmful effect.
The Emotional Experience of Receiving a VUS Report
The psychological impact of receiving a VUS report is distinctly different from a clear positive or negative result. Many people describe it as a feeling of being suspended in mid-air. They are unable to feel fully reassured, yet with nothing concrete to act upon. It is, in many ways, like standing in a thick fog.
Clinical experience shows that prolonged uncertainty can sometimes be harder to bear than a definitive bad result, because a clear diagnosis at least provides a direction for action. A VUS, by contrast, removes that sense of direction entirely.
Common psychological responses to a VUS include: adopting the reassuring belief that “unclear means fine,” spiralling anxiety from repeated online searches, and regret about having undergone genetic testing at all. All of these reactions are a normal part of the psychological adjustment process.
Acknowledging the emotional weight of this experience is the first step toward navigating the grey zone. The value of genetic counselling lies not only in conveying scientific information, but equally in accompanying individuals through uncertainty — helping them find psychological footing when the ground feels unstable.
The Clinical Boundaries of VUS: What Decisions Should Not Be Based on a VUS?
Until a VUS is reclassified, it cannot form the basis of any major clinical or medical decision. This is a fundamental principle of clinical genetics and an essential safeguard against the harm caused by misdiagnosis.
In the context of reproductive decision-making, neither preimplantation genetic testing (PGT) nor prenatal diagnosis should use a VUS as a basis for screening. Since the variant may be entirely benign, using it to exclude embryos carries the risk of discarding a completely healthy life.
It is not recommended to proactively screen healthy family members for a VUS. Without being able to offer any meaningful guidance based on the result, doing so only introduces unnecessary anxiety into the family without any actionable basis.
For VUS findings in cancer susceptibility genes (such as those associated with breast or ovarian cancer), prophylactic surgery or other aggressive medical interventions should never be recommended on this basis alone, as current evidence is insufficient to confirm any elevated cancer risk.
These boundaries are rooted in the foundational principle of medical ethics: “First, do no harm” — in the absence of sufficient evidence, taking action carries a risk of harm that is likely to outweigh any potential benefit.
A VUS Is Not a Static Label: The Possibility and Conditions for Reclassification
A VUS classification is not permanent. As scientific research progresses, a variant that is “uncertain” today may be reclassified as “likely benign” or “likely pathogenic” within a matter of years — some of the fog does, eventually, clear.
The forces driving reclassification come from two primary directions: first, the continuous expansion of global genetic databases, as laboratories worldwide add new patient data and functional study results; and second, updates to an individual’s own clinical information, including newly emerging symptoms or newly diagnosed family members.
Personal clinical data holds immense value in VUS research. A limited number of documented cases is often the very factor holding back a reclassification, meaning that each carrier’s information could be the final piece of evidence that tips the scales.
This means that individuals living with a VUS are not passive bystanders — they are active participants in the ongoing tracking process. Any new developments in personal health or family medical history should be communicated promptly to a genetic counsellor or clinical genetics service, rather than waiting for a scheduled appointment.
Long-Term Support Through Genetic Counselling: “Every 2 to 5 Years, Let’s Check In”
The most important clinical recommendation a genetic counsellor can offer a VUS carrier is to establish a structured long-term review plan, returning every 2 to 5 years. This timeframe aligns with the pace of scientific advancement and the rate at which meaningful clinical information tends to accumulate.
Each review covers three core areas: updating scientific knowledge (has there been any new research on this VUS?), updating personal clinical information (any changes in health status or family history?), and reassessing whether any adjustments are now warranted.
Throughout this ongoing relationship, a genetic counsellor plays several distinct and complementary roles:
Knowledge translator — tracking the latest scientific developments, filtering and synthesising what is relevant, and communicating it in accessible, meaningful terms at the right time.
Emotional companion — offering a professional, non-judgmental space where anxiety, frustration, and hope can all be held and acknowledged without pressure or judgement.
Decision-making partner — helping individuals identify what remains within their control during a period of uncertainty, and working alongside them — guided by their values and life priorities — to find the areas where they can take meaningful steps forward.
The guiding belief of genetic counselling in this context is: “We may not have the answer right now, but we can learn together how to live with not knowing. The absence of a clear result does not mean the absence of choice in the rest of your life.”
Next Episode: My Genetic Counselor Study Note: Things that nobody told me before entering this profession.
GENE TALKS Podcast Disclaimer
The content of this podcast is provided for general educational and informational purposes only and does not constitute medical advice, diagnosis, or treatment of any kind.
If you have questions about your personal health, genetic test results, or medical decisions, you should consult a qualified healthcare or genetics professional.
Any cases, experiences, or opinions mentioned in this program reflect the personal views of the host, and do not represent the positions of any medical institutions or professional organisations.
While GENE TALKS and its host endeavor to provide accurate and reliable information, they are not responsible for any consequences arising from the use or interpretation of the content.
Our mission: to help you understand genetics — and yourself — not to replace professional judgment.