Fluoropyrimidine (5-FU) toxicity risk

DPYD breaks down the chemotherapy drugs 5-fluorouracil and capecitabine. A no-function variant lets these drugs accumulate to dangerous levels, risking severe toxicity.

What DPYD*2A does

DPYD makes dihydropyrimidine dehydrogenase, the enzyme that clears more than 80% of a dose of fluorouracil or capecitabine from the body. This variant, known as *2A, sits at a splice site and eliminates that allele's function entirely.

With one working copy instead of two, standard chemotherapy doses accumulate. With neither, they accumulate severely. This is the mechanism behind the most dangerous drug reaction on this site.

Why this one is different from everything else here

Most results on this site shift a probability. This one can change a chemotherapy dose. Severe and occasionally fatal toxicity, including profound drops in blood counts, mucositis and diarrhoea, has been documented in carriers given standard fluoropyrimidine doses.

CPIC rates the evidence level A and recommends reducing the starting dose by about half in people with one non-functional copy, with subsequent titration, and avoiding fluoropyrimidines in people with two. Pre-treatment DPYD testing before fluorouracil or capecitabine is now standard practice across the UK and much of Europe.

How strong the evidence is

ClinVar records it as a drug-response variant with three-star review status and 30 submitters, under dihydropyrimidine dehydrogenase deficiency and fluorouracil response. It also shows up biochemically: in a study of 6,136 people, the variant was strongly associated with blood uracil levels, which is the substrate the enzyme clears and the basis of the phenotype test used alongside genotyping.

How common it is, and what a normal result leaves open

It is rare. In 1000 Genomes reference data roughly 1% of European-ancestry individuals carry one copy, and it is close to absent in East Asian, South Asian and African-ancestry samples.

That rarity is exactly why a reassuring result here means less than it appears. *2A is one of four DPYD variants that guidelines test, alongside *13, c.2846A>T and the HapB3 haplotype, and none of the others are read here. Clinical DPYD testing covers all of them, and even a full panel does not exclude every cause of DPD deficiency.

What to do with this result

If you are ever prescribed fluorouracil, capecitabine or tegafur, tell your oncology team that a consumer test flagged DPYD*2A, and let them do the clinical test. Nothing about this belongs in a self-directed decision, and the clinical pathway already exists.

If you are not facing fluoropyrimidine chemotherapy, this result changes nothing today. It is worth recording somewhere you will find it again.

What each rs3918290 genotype means

rs3918290 has three possible genotypes: CC, CT and TT.

Normal 5-FU breakdown (rs3918290 CC). You don't carry the no-function DPYD variant, so the enzyme that breaks down the chemotherapy drugs 5-fluorouracil and capecitabine works normally as far as this gene goes. These drugs should clear at the usual rate (other DPYD variants aren't covered here).

Higher 5-FU toxicity risk (rs3918290 CT). You carry one non-working copy of DPYD, so you break down the chemo drugs 5-fluorouracil and capecitabine more slowly. If you ever need these specific chemotherapies, this genotype is important, since a reduced dose is usually recommended to avoid severe side effects. It only matters in that context.

High 5-FU toxicity risk (rs3918290 TT). You have two non-working copies of DPYD and make little or none of the enzyme that clears 5-fluorouracil and capecitabine. These chemo drugs could reach dangerous levels, so they're generally avoided or used only with major dose changes. This is critical information if cancer treatment ever comes up.

Evidence & sources

Across global populations, fewer than 1% of people carry two copies of this variant, and about 99% carry none.

CPIC provides dosing guidance for fluorouracil based on this gene.

This variant appears in 1 published genetic study: PubMed 35347128.

Common questions

How serious is this really? For someone about to receive fluorouracil or capecitabine, seriously enough that pre-treatment testing is now routine in the UK and much of Europe, because carriers given standard doses have suffered severe and occasionally fatal toxicity. Outside that setting, the variant has no effect on daily life.

Does a normal result mean I can take 5-FU safely? No. This reads one of the four DPYD variants that clinical testing covers, and DPD deficiency has other causes still. Oncology teams use their own testing, which is what your treatment should rest on.

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