Every human being has genetic differences. In fact, each of us carries millions of variations in our DNA compared to the reference human genome [1].

Most of these variations are completely harmless. Some may influence traits like height or metabolism. A small percentage may contribute to disease.

To standardize interpretation, variants are classified according to internationally accepted guidelines from the American College of Medical Genetics and Genomics (ACMG) into five categories [2]:

1. Pathogenic – Disease causing
2. Likely Pathogenic – Very likely to be disease causing
3. Variant of Uncertain Significance (VUS)
4. Likely Benign – Probably not harmful
5. Benign – Harmless

A VUS is in the grey zone.

The science of genetics is still evolving. There are several reasons why a variant may be labeled “uncertain”:

• Limited Scientific Evidence

Some variants are rare. If only a few individuals worldwide have been reported with that change, there may not be enough data to determine whether it causes disease.

• Underrepresentation of Certain Populations

Most genomic databases have historically been built using European populations [3]. Variants common in South Asian or Indian populations may appear “rare” simply because they are underrepresented in global databases.

This is especially relevant for your practice in India.

• Newly Identified Genes

Some genes are newly associated with disease. As research evolves, interpretations change.

Did You Know?

Studies show that the rate of VUS findings can range from 10% to over 30% depending on the type of test and population studied [4].
Whole exome sequencing and large cancer panels tend to have higher VUS rates.

No.

A VUS should not be used to confirm a diagnosis [2].

Medical decisions — including surgery, chemotherapy, reproductive planning, or pregnancy termination, should not be based solely on a VUS result.

Instead, interpretation must include:

• Clinical symptoms
• Family history
• Other laboratory findings
• Segregation analysis (testing family members when appropriate)

In many cases, a VUS turns out to be benign.

Genetics is not static.

Variants are periodically re-evaluated as new research emerges. Large laboratories routinely update classifications based on:

• Population frequency data
• Functional studies
• Published case reports
• Family segregation analysis

Research shows that the majority of reclassified VUS are downgraded to benign or likely benign [5].

Only a small percentage are upgraded to pathogenic.

This is why follow-up with a genetic counselor is important.

Even when explained properly, uncertainty can feel heavy.

Patients often experience:

• Anxiety
• Frustration
• Fear of “something being missed”
• Guilt about passing something to children

In prenatal settings, this stress can be amplified. In cancer genetics, it can lead to unnecessary fear about risk.

Genetic counseling helps place the result in context — preventing overreaction while ensuring appropriate monitoring.

• Prenatal Testing

When chromosomal microarray or exome sequencing is performed during pregnancy, a VUS may be identified.

In these situations:

• Additional parental testing may help clarify significance.
• Most VUS do not lead to structural anomalies.
• Clinical correlation with ultrasound findings is essential [6].

Careful counseling is critical to avoid unnecessary decisions based on uncertain data.

• Cancer Genetic Testing

Multigene cancer panels frequently identify VUS, particularly in genes like BRCA2, ATM, CHEK2, and others [7].

Important principle:
A VUS in a cancer gene does not mean increased cancer risk unless reclassified as pathogenic.

Clinical management should follow personal and family history — not the VUS alone.

• Neurodevelopmental Disorders

Exome testing in children with developmental delay or epilepsy often reveals VUS [8].

Sometimes, parental testing helps determine whether:

• The variant is inherited from a healthy parent (suggesting benign nature), or
• It is de novo (new), which may warrant closer evaluation.

Yes, in some scenarios.

Testing parents or other relatives may clarify:

• Whether the variant segregates with the condition
• Whether it appears in unaffected individuals

However, not all VUS require family testing. The decision should be guided by a genetic counselor.

This is where genetic counseling becomes essential.

A genetic counselor helps you:

✔ Understand what the VUS does and does not mean
✔ Avoid unnecessary medical interventions
✔ Decide whether additional testing is needed
✔ Manage emotional stress
✔ Plan appropriate follow-up

Pre-test counseling is equally important. When patients are informed beforehand that uncertain results are possible, the emotional impact is much lower [9].

Read more about the process of Genetic counseling in our previous blog post here.

Receiving a “Variant of Uncertain Significance” can feel unsettling. But uncertainty is not the same as danger.

A VUS is a temporary label, a placeholder in scientific understanding.

With proper interpretation, follow-up, and guidance from a genetic counselor, families can move forward with clarity rather than fear.