Variants of Uncertain Significance — How to Think About Them

A variant of uncertain significance (VUS) is a genetic finding where the lab sees a change in the DNA, but science cannot yet classify it as:

• harmful (pathogenic)
• harmless (benign)

It is the genetic equivalent of:
“Something is here, but we don’t know if it matters.”

Because VUS findings are common—especially in expanded carrier screening and large gene panels—they often cause anxiety but rarely change medical decisions.

Key truths:

• A VUS is not a diagnosis
• A VUS is not something you “carry” in a harmful sense
• A VUS does not justify PGT-M
• A VUS is not used to exclude embryos
• Many VUS are reclassified to benign over time

What matters is understanding the VUS, so you don’t overreact, delay treatment, or spend money on unnecessary testing.

Who It Helps

Genetic counseling around VUS is most useful when:

• You are worried the VUS might affect embryo health
• You’re unsure whether your partner needs matching gene testing
• You have a personal or family history of a related disease
• You’re considering PGT-M and need to know if a VUS qualifies (it usually does not)
• You’re deciding whether to proceed with IVF, IUI, or natural conception
• You received conflicting interpretations from different labs

When counseling may not be necessary:

• You have a VUS in a recessive gene, your partner is negative, and there’s no family history
• The VUS is in a gene unrelated to your concerns
• Your clinic already reviewed it and confirmed it does not change the plan

Step-by-Step

A simple sequence to reduce stress and prevent unnecessary delays:

1. Collect results

   • Carrier screening

   • PGT reports

   • Family history

   • Any past genetic testing

2. Identify the gene and condition

   • Is the condition recessive, dominant, X-linked?

   • Is it severe or mild?

3. Assess relevance

   • Does the VUS match your symptoms or history?

   • Does your partner need targeted testing for the same gene?

4. Decision checkpoint

   • Does the VUS change the fertility plan?

   • Almost always, the answer is no.

5. Document and move forward

   • Save the report in case the variant is reclassified later

   • Proceed with IVF, IUI, or embryo transfer without delay

This sequence keeps timelines intact and prevents spiraling into worst-case scenarios.

Pros & Cons

Pros of Understanding VUS Clearly

• Avoid unnecessary PGT-M setup
• Prevent IVF cycle delays
• Avoid partner testing unless it impacts actual risk
• Reduce anxiety with clear context
• Stop overinterpretation that can cost money and time

Cons / Limitations

• VUS cannot be definitively interpreted
• Labs may change classification years later
• Can generate fear despite being clinically low-impact
• Some clinicians over-order follow-up testing

Costs & Logistics

While a VUS itself does not cost money, misunderstandings around it can.

Possible cost drivers:

• Genetic counseling fee: ₹4,000–₹12,000 (or $75–$250 internationally)
• Unnecessary partner testing: avoid unless recommended
• Unnecessary PGT-M setup: usually ₹75,000–₹150,000+ (or $1,500–$3,000)
• Cycle delays: indirect emotional and financial costs

Simple tracking to avoid surprise bills:

• Confirm whether partner testing is needed
• Clarify if the VUS changes the treatment plan
• Document classification for future reference
• Avoid labs or panels that add no actionable value

What Improves Outcomes

Actions that actually matter:

• Contextualizing the VUS with a fertility-focused genetic counselor
• Understanding inheritance patterns before panicking
• Coordinating partner testing only when relevant
• Avoiding PGT-M unless a pathogenic variant is confirmed
• Planning IVF timelines before testing so you don’t get stuck waiting

Actions that rarely matter:

• Testing extended family members “just to check”
• Repeating the same test within months
• Embryo testing for a VUS
• Changing fertility plan solely based on VUS findings

Case Study

From uncertainty to clarity with structured thresholds

A patient completes expanded carrier screening and receives a VUS in a recessive metabolic gene.
She panics, thinking she must avoid transferring embryos.

During genetic counseling:

• Counselor clarifies the condition is recessive, so partner testing is needed only for the same gene
• Partner tests negative
• Risk becomes effectively zero
• No need for PGT-M
• No effect on embryo selection
• IVF cycle proceeds on schedule

Outcome:

• Anxiety reduced
• No expensive add-on tests
• No delays
• Understanding of true risk → confidence in transferring embryos

Mistakes to Avoid

• Treating a VUS like a harmful mutation
• Ordering partner testing for unrelated genes
• Setting up PGT-M for a VUS (labs won’t do it anyway)
• Delaying embryo transfer while waiting for reclassification
• Assuming a VUS explains miscarriages or infertility
• Confusing VUS with mosaicism on PGT-A
• Not uploading results before a counseling session

FAQs

Q. Is a VUS dangerous?

Ans : Not known to be—and most later become classified as benign.

Q. Does a VUS require PGT-M?

Ans : No. PGT-M is only for confirmed pathogenic variants.

Q. Can a VUS cause infertility?

Ans : Almost never. VUS have low clinical impact.

Q. Should my partner get tested?

Ans : Only if the VUS is in a recessive gene and relevant to reproductive risk.

Q. Can the VUS affect embryo health?

Ans : Not with current evidence. Embryos are not excluded for VUS.

Q. Can it change over time?

Ans : Yes—labs sometimes reclassify. Keep the result on file.

Next Steps

• Free 15-min nurse consult
• Upload your labs
• Get a personalized cost breakdown for your case

Related Links

• Genetic testing carrier
• Intended Parents
• Become a Surrogate
• Fixed‑Cost Packages
• SART
• CDC ART
• ASRM