When “Factor V” Doesn’t Include Factor V Leiden: A Genomics Reporting Problem Patients Should Understand

Genomic testing is often presented as comprehensive, precise, and definitive. Patients increasingly rely on genomic reports to better understand inherited disease risk, medication response, and long-term health planning.

But one important reality is rarely discussed clearly enough:

Not all genomic reports analyze the same variants — even within the same gene.

I recently discovered this firsthand when reviewing a genomic report that included the F5 gene in the reportable scope, but explicitly excluded analysis of the Factor V Leiden variant (F5 c.1601G>A) — one of the most clinically recognized thrombophilia-associated variants.

To be clear, this is not an accusation of misconduct. The exclusion was technically disclosed, though it appeared in supplementary website content rather than prominently in the clinical report itself.

The larger issue is something far more important for the genomics industry:

Most patients — and many clinicians — may not fully understand what those exclusions actually mean.

And in genomics, what is not analyzed can matter just as much as what is.

The Confusion Around “Factor V”

The website for the company included the following statement:

“Factor V deficiency is a rare bleeding disorder that affects blood clotting… Analysis does not include the Factor V Leiden variant.”

Scientifically, this distinction is valid.

These are different conditions involving the same gene:

• Factor V deficiency → a bleeding disorder
• Factor V Leiden → a thrombophilia (increased clotting tendency)

But from a patient interpretation standpoint, this creates a significant communication challenge. Most people reading a genomic report will see:

• “Factor V”
• discussion of blood clotting
• genetic analysis of the F5 gene

and reasonably assume major clinically relevant F5 variants were evaluated.

In this case, they were not.

The Bigger Problem in Genomics Reporting

This experience reinforced something the genomics industry needs to communicate more clearly:

A genomic report is not necessarily a comprehensive analysis of every clinically relevant variant associated with a gene.

Many genomic platforms limit analysis scope, focus on specific disorders, exclude certain variants intentionally, prioritize wellness over clinical risk, or restrict reporting to predefined categories.

All of this may be scientifically defensible.

But the practical problem is that users often interpret genomic reports as broader and more comprehensive than they actually are.

Why Would a Company Exclude Factor V Leiden?

There are several legitimate reasons why a genomics company might intentionally exclude Factor V Leiden analysis:

1. Scope Definition

The report may specifically target bleeding disorders rather than thrombophilia risk. Since Factor V Leiden causes increased clotting rather than bleeding, it may fall outside the intended analysis framework.

2. Regulatory and Clinical Constraints

Some organizations avoid reporting medically actionable variants unless confirmatory clinical testing is available, genetic counseling infrastructure is in place, regulatory standards are met, or the assay has been clinically validated for that purpose. This is especially relevant for variants that may influence: anticoagulation decisions, surgical planning, pregnancy management, or thrombosis risk assessment.

3. Product Positioning

Not all genomic products are designed as clinical diagnostic tools. Some prioritize wellness insights, educational genetics, ancestry, lifestyle interpretation, and limited trait analysis. The distinction between “consumer genomic reporting” and “clinical genomic interpretation” is often less obvious to users than it should be.

Based on the product positioning and available documentation, the rationale for excluding Factor V Leiden analysis is not immediately obvious. The exclusion becomes more notable when considering the variant's clinical significance.

The Variant

The global allele frequency of F5 c.1601G>A (p.Arg534Gln) NM000130.4 is ~2% (see gnomAD), with some populations reporting frequencies as high as 9%. Although its relatively high population frequency introduces nuances into ACMG-style rare-disease interpretation frameworks, Factor V Leiden remains one of the most clinically established inherited thrombophilia risk variants. Gain-of-function variants in the F5 gene are associated with an autosomal dominant susceptibility to thrombophilia (MIM 188055), recurrent pregnancy loss (MIM 614389), and autosomal recessive Budd-Chiari syndrome (MIM 600880). Thrombophilia is characterized by a tendency to form abnormal blood clots, which increases the risk of venous thromboembolism. This becomes especially relevant in IVF and reproductive medicine. Studies and guidelines consistently show IVF increases venous thromboembolism (VTE) risk, particularly during the first trimester and especially in patients with Ovarian Hyperstimulation Syndrome, which can be a complication of fertility treatments, or inherited thrombophilias like Factor V Leiden.

Given the clinical relevance and population frequency of Factor V Leiden, its exclusion raises important questions about how genomic reporting scope is determined and communicated to users.

Excluding Factor V Leiden analysis may not matter for a wellness report — but it can become relevant in contexts like IVF planning, pregnancy risk assessment, estrogen exposure, and thrombosis prevention.

Relevance

People who are heterozygous for the Factor V Leiden variant often live completely normal lives and never experience a clotting event, but the variant does increase susceptibility to venous thromboembolism under certain circumstances (see Mayo Clinic). The risk becomes more clinically relevant during situations that already predispose the body to clot formation, including long-haul travel, surgery, immobilization, major illness, estrogen exposure, pregnancy, or IVF treatment. Because of this, awareness and prevention are usually more important than aggressive treatment in otherwise healthy heterozygous individuals. I am aware of this because I am heterozygous for this variant and have a family history of venous thrombosis. Our Simplify Genomics report highlights this for me in both the hereditary disease risk and polygenic risk sections.

Further, our Simplify Genomics report includes pharmacogenomics reporting that my physician can use if they decide to prescribe Warfarin or other anticoagulants used to treat venous thromboembolism.

This is the level of comprehensive genomic interpretation many patients assume they are receiving when they purchase whole genome analysis.

Genomics Needs Better Transparency

The genomics industry has made remarkable advances in accessibility and affordability, and, to a large extent, we are seeing the benefits for patients. However, as an industry, we need to be more transparent about the limitations of our testing and the scope of our work.

Reports should make it easier for users to understand:

• What was analyzed
• What was excluded
• Why certain variants were omitted
• What the clinical limitations are
• Whether findings are diagnostic, educational, or informational only

Because in genomics:

Absence of evidence is not evidence of absence.

Final Thoughts

My experience with the excluded Factor V Leiden variant highlighted an important reality about modern genomics:

Two reports discussing the same gene may not evaluate the same risks.

And unless users understand those distinctions clearly, genomic reporting can unintentionally create confidence in conclusions that were never actually tested.

As genomic medicine becomes increasingly mainstream, transparency about what was not analyzed may ultimately prove just as important as the findings reported in the report itself.