How can I use clinical genomics labs to compare sequencing results when evaluating a diagnosis with my doctor?

You can use clinical genomics labs as a comparison point when reviewing possible diagnoses with your doctor, but the key is to compare the same type of test, the same variant classification standards, and the same clinical question. Here’s a practical way to do it.

1) Start with the exact clinical question

Ask your doctor:

• What diagnosis are we trying to confirm or rule out?
• Which genes or variant types matter most?
• Is the goal diagnosis, carrier status, risk prediction, or treatment guidance?

This matters because different labs may test different things:

• Single-gene tests
• Panel tests for a set of related conditions
• Exome sequencing
• Genome sequencing
• CNV/structural variant analysis
• Mitochondrial testing
• Repeat expansion testing
  A result can look “different” simply because one lab looked for a variant type the other did not.

2) Compare the lab methods, not just the final report

When comparing results, ask for these details from each lab:

• Genes covered
• Coverage depth / quality
• Whether deletion/duplication testing was included
• Whether intronic or noncoding regions were analyzed
• Variant classification framework used
• Date of report (classifications can change)
• Reference genome build and transcript used

Two reports may disagree because one lab has better detection or because one used an older classification.

3) Focus on variant classification

Clinical labs typically classify variants as:

• Pathogenic
• Likely pathogenic
• VUS (variant of uncertain significance)
• Likely benign
• Benign

For diagnosis, the most important questions are:

• Is the same variant being reported?
• Did both labs call it pathogenic/likely pathogenic, or is one calling it a VUS?
• Did one lab explain the evidence differently?

If one lab reports a VUS and another reports the same variant as likely pathogenic, that’s a sign to ask for:

• The lab’s evidence summary
• Whether a reanalysis or second review is possible
• Whether a genetics specialist can reconcile the interpretation

4) Ask for the full report and raw data if needed

To compare properly, request:

• The full clinical report from each lab
• The variant list with genomic coordinates
• Any supplementary evidence or classification notes
• If appropriate, whether raw sequencing data or a BAM/VCF file can be shared with another clinician or lab

A genetics clinic or medical geneticist can help interpret this, especially if the two tests were done at different labs.

5) Use a third-party clinical genetics review if results conflict

If the results are confusing or discordant:

• Ask for referral to a clinical geneticist or genetic counselor
• Consider a send-out review at a larger reference lab
• Ask whether the variant should be reviewed in a multidisciplinary case conference
• If needed, request orthogonal confirmation such as Sanger sequencing, MLPA, qPCR, or another validated method

6) Compare with phenotype, not just sequence

A diagnosis is strongest when sequencing matches your symptoms and family history. Ask:

• Does this variant fit the clinical picture?
• Is the gene known to cause the condition suspected?
• Is inheritance consistent with the family history?
• Are there other explanations for the symptoms?

If the sequence result doesn’t fit the phenotype, the diagnosis may still be uncertain even if a variant is present.

7) Be aware of labs’ limitations and differences

Clinical genomics labs differ in:

• How they detect copy-number changes
• Whether they detect mosaicism
• Their handling of GC-rich or repetitive regions
• Their reclassification policies
• How often they update old reports

A negative result from one lab doesn’t always mean the condition is excluded.

8) A good way to talk to your doctor

You can say:

“I’d like help comparing these two genetic test reports. Can we review whether they tested the same genes and variant types, and whether the variant classification is consistent with my symptoms?”

Or:

“Should we ask a clinical genetics lab or genetic counselor to review both reports side by side?”

9) Questions to ask your doctor or genetic counselor

• Were these tests designed to answer the same question?
• Did both labs analyze the same genes and variant types?
• Are the reported variants identical by genomic coordinates?
• Is the variant classification concordant?
• Would a genetics specialist recommend reanalysis or confirmatory testing?
• Should we test another family member to help interpret the result?

10) Important caution

Direct-to-consumer or research sequencing results usually should not be used alone to make a diagnosis. For medical decisions, comparisons should be based on CLIA-certified / accredited clinical lab reports and reviewed by your clinician.

If you want, I can also help you build a side-by-side comparison checklist for two genetic reports that you can bring to your doctor.