rs3918290 — DPYD *2A

Most critical pharmacogenomic variant causing complete loss of DPD enzyme function; increases fatal 5-FU/capecitabine toxicity risk 25-fold without dose reduction

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DPYD*2A — The Most Critical Pharmacogenomic Variant

DPYD encodes dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme11 rate-limiting enzyme
DPD catabolizes 80-90% of administered 5-fluorouracil into inactive metabolites responsible for breaking down fluoropyrimidine chemotherapy drugs. The DPYD*2A variant (also known as IVS14+1G>A) is a 22 G-to-A transition at the invariant splice donor site of intron 14, causing complete skipping of exon 14 splice site mutation that results in complete loss of enzyme function. This is the single most important pharmacogenomic variant to test before starting fluoropyrimidine-based cancer treatment.

The Mechanism

The DPYD gene spans 950 kb on 33 chromosome 1p22 with 23 coding exons encoding the 1025 amino acid DPD enzyme chromosome 1. The *2A variant occurs at the 44 The +1 position of the splice donor site — the invariant GT dinucleotide essential for proper mRNA splicing splice donor site immediately after exon 14, disrupting the normal splicing machinery. Without the correct splice signal, the entire exon 14 (165 base pairs) is 55 RT-PCR analysis on patient RNA demonstrated complete exon 14 skipping resulting in an in-frame deletion of 55 amino acids skipped during mRNA processing, producing a truncated, catalytically inactive protein.

Functional studies66 Functional studies
Patient fibroblasts homozygous for *2A showed undetectable DPD enzyme activity; heterozygotes had approximately 50% activity have confirmed that homozygous *2A carriers have zero measurable DPD activity, while heterozygous carriers retain approximately 50% of normal enzyme function. Without sufficient DPD to metabolize fluoropyrimidines, these drugs accumulate to toxic levels, causing severe bone marrow suppression, gastrointestinal toxicity, and in 2-4% of variant carriers receiving standard doses, 77 death.

The Evidence

The clinical significance of DPYD*2A is 88 supported by CPIC Level 1A evidence: variant-specific prescribing guidance in current clinical guidelines with PharmGKB Level 1A annotation thoroughly established across multiple lines of evidence. A 2021 meta-analysis99 A 2021 meta-analysis
Pooled data from 13,929 patients showing carriers had 25.6-fold increased risk of treatment-related death (95% CI 12.1-53.9) of 13,929 cancer patients found that *2A carriers receiving standard-dose fluoropyrimidines had a 25.6-fold increased risk of treatment-related death compared to non-carriers. Without dose adjustment, heterozygous *2A carriers experience severe toxicity in 1010 73-77% of cases, compared to 20-30% in the general population.

Prospective implementation trials1111 Prospective implementation trials
Henricks et al. 2018 study of 1,103 patients with pre-treatment DPYD genotyping and dose adjustment have proven that genotype-guided dosing solves this problem. In a landmark 2018 study of 1,103 patients, preemptive 50% dose reduction in *2A carriers reduced severe toxicity from 73% to 31% — nearly normalizing risk to that of non-carriers. Critically, 1212 matched pair analysis showed no difference in overall survival or progression-free survival between dose-reduced carriers and full-dose non-carriers survival outcomes remained equivalent: dose-reduced *2A carriers had the same overall survival and progression-free survival as non-carriers receiving full doses.

Based on this evidence, the Clinical Pharmacogenetics Implementation Consortium1313 Clinical Pharmacogenetics Implementation Consortium
CPIC 2017 guideline with 2018 update recommending 50% dose reduction for intermediate metabolizers (CPIC) issued Level A guidelines in 2017 (updated 2018) for DPYD-guided fluoropyrimidine dosing. The 1414 European Medicines Agency mandated DPD testing before fluoropyrimidine treatment in 2020; UK NHS implemented national DPYD testing in 2020 European Medicines Agency (2020) and UK National Health Service (2020) now mandate or strongly recommend pre-treatment DPYD testing.

Practical Implications

If you are being prescribed 5-fluorouracil (5-FU), capecitabine (Xeloda), or tegafur for cancer treatment, DPYD genotyping is essential before starting therapy. These drugs are backbone treatments for colorectal, breast, gastric, pancreatic, and head-and-neck cancers. The standard approach is straightforward:

For heterozygous (*2A) carriers (CT genotype): Start at 50% of the standard dose, then titrate upward based on tolerability and therapeutic drug monitoring. Your oncologist should measure 5-FU plasma levels to ensure you're achieving therapeutic concentrations without toxicity. Most carriers can eventually increase to 65-80% of standard doses.

For homozygous carriers (TT genotype) or compound heterozygotes: Fluoropyrimidines are 1515 FDA label states no dose of fluorouracil has been proven safe in individuals with absent DPD activity contraindicated — no dose has been proven safe. Your oncologist must choose an alternative chemotherapy regimen. There is an 1616 FDA-approved antidote uridine triacetate for emergency rescue from 5-FU overdose FDA-approved antidote (uridine triacetate) for emergency overdose situations, but prevention through genotyping is far preferable.

Testing is now routine in Europe but remains inconsistent in North America. If your oncologist hasn't ordered DPYD testing, request it explicitly. Most genetic testing companies offer targeted DPYD panels covering *2A plus the other three clinically actionable variants (c.1679T>G, c.2846A>T, c.1236G>A/HapB3). Turnaround time is typically 2-5 days. The test is cost-effective: preventing even one case of severe toxicity saves $155,000-180,0001717 $155,000-180,000
Cost of managing severe fluoropyrimidine toxicity including hospitalization and rescue therapy in healthcare costs compared to ~$160-250 for genotyping.

Interactions

DPYD*2A is one of four "high-priority" DPYD variants routinely tested before fluoropyrimidine therapy. The other three are rs55886062 (DPYD*13, c.1679T>G), rs67376798 (c.2846A>T), and rs75017182 (HapB3 haplotype). Each contributes additively to DPD deficiency. Approximately 0.07% of patients are compound heterozygotes, carrying two different DPYD risk variants simultaneously. In compound heterozygous states (e.g., *2A plus c.2846A>T), the combined enzyme deficiency may approach homozygous levels, requiring fluoropyrimidine avoidance rather than dose reduction. If testing reveals multiple DPYD variants, discuss with your oncology team immediately — this dramatically changes dosing strategy.

Some cancer centers also test for rare variants like c.557A>G (more common in individuals of African ancestry) or perform DPYD sequencing to capture novel loss-of-function mutations. While *2A, *13, c.2846A>T, and HapB3 account for the majority of predicted DPD deficiency, additional variants continue to be discovered.

Drug Interactions

fluorouracil (5-FU) increased_toxicity CPIC
capecitabine increased_toxicity CPIC
tegafur increased_toxicity CPIC

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal Metabolizer Normal

Normal DPD enzyme activity — standard fluoropyrimidine dosing is safe

You have two normal copies of the DPYD gene, which means your body produces fully functional dihydropyrimidine dehydrogenase (DPD) enzyme at normal levels. DPD breaks down fluoropyrimidine chemotherapy drugs at the expected rate. Approximately 99.5% of people of European descent share this genotype. If you require treatment with 5-fluorouracil, capecitabine, or tegafur, standard dosing protocols are appropriate and safe for you.

CC Normal Metabolizer Normal

Normal DPD enzyme activity — standard fluoropyrimidine dosing is safe

You have two normal copies of the DPYD gene, which means your body produces fully functional dihydropyrimidine dehydrogenase (DPD) enzyme at normal levels. DPD breaks down fluoropyrimidine chemotherapy drugs at the expected rate. Approximately 99.5% of people of European descent share this genotype. If you require treatment with 5-fluorouracil, capecitabine, or tegafur, standard dosing protocols are appropriate and safe for you.

AG Intermediate Metabolizer Reduced

50% reduced DPD activity — requires 50% dose reduction to prevent life-threatening toxicity

The DPYD*2A splice site mutation causes complete skipping of exon 14 during gene transcription, producing a truncated, inactive protein from the affected allele. Your one normal allele provides only 50% of typical DPD enzyme activity. Because DPD catabolizes 80-90% of administered fluoropyrimidines, reduced enzyme activity causes drug accumulation to toxic levels. Standard-dose treatment in AG carriers results in 5-FU plasma concentrations 2-3 times higher than in normal metabolizers, overwhelming bone marrow and gastrointestinal tissues.

Large prospective trials have established that a 50% initial dose reduction normalizes drug exposure and dramatically reduces toxicity without compromising efficacy. In the Henricks et al. 2018 study, *2A carriers receiving 50% dose reductions had equivalent overall survival and progression-free survival compared to non-carriers receiving full doses. This is now considered the standard of care in Europe, with mandatory or strongly recommended pre-treatment testing.

Your oncologist should use therapeutic drug monitoring (measuring 5-FU plasma levels) to guide gradual dose escalation. Many *2A carriers can eventually tolerate 65-80% of standard doses once steady-state drug levels are confirmed to be in the therapeutic range without excessive toxicity. This individualized approach maintains treatment effectiveness while preventing the severe myelosuppression, mucositis, and diarrhea that occur with standard dosing.

CT Intermediate Metabolizer Reduced

50% reduced DPD activity — requires 50% dose reduction to prevent life-threatening toxicity

The DPYD*2A splice site mutation causes complete skipping of exon 14 during gene transcription, producing a truncated, inactive protein from the affected allele. Your one normal allele provides only 50% of typical DPD enzyme activity. Because DPD catabolizes 80-90% of administered fluoropyrimidines, reduced enzyme activity causes drug accumulation to toxic levels. Standard-dose treatment in CT carriers results in 5-FU plasma concentrations 2-3 times higher than in normal metabolizers, overwhelming bone marrow and gastrointestinal tissues.

Large prospective trials have established that a 50% initial dose reduction normalizes drug exposure and dramatically reduces toxicity without compromising efficacy. In the Henricks et al. 2018 study, *2A carriers receiving 50% dose reductions had equivalent overall survival and progression-free survival compared to non-carriers receiving full doses. This is now considered the standard of care in Europe, with mandatory or strongly recommended pre-treatment testing.

Your oncologist should use therapeutic drug monitoring (measuring 5-FU plasma levels) to guide gradual dose escalation. Many *2A carriers can eventually tolerate 65-80% of standard doses once steady-state drug levels are confirmed to be in the therapeutic range without excessive toxicity. This individualized approach maintains treatment effectiveness while preventing the severe myelosuppression, mucositis, and diarrhea that occur with standard dosing.

AA Poor Metabolizer Absent

Complete DPD deficiency — fluoropyrimidines are contraindicated and potentially fatal

With two non-functional DPYD*2A alleles, you produce no active DPD enzyme. Studies of homozygous *2A patients show undetectable enzyme activity and inability to convert 5-FU to inactive metabolites. Without metabolism, fluoropyrimidines accumulate to lethal concentrations, causing rapid-onset pancytopenia (complete bone marrow shutdown), severe mucositis throughout the GI tract, and multi-organ toxicity. Multiple case reports document fatalities in homozygous DPYD*2A patients who received even fractions of standard fluoropyrimidine doses.

The FDA drug label explicitly states: "No dose of fluorouracil has been proven safe in individuals with absent DPD activity." There are case reports of attempted ultra-low-dose regimens (5-10% of standard) in compound heterozygotes with near-complete deficiency, but these remain experimental and carry high risk. The established standard of care is to avoid fluoropyrimidines entirely and select alternative chemotherapy regimens.

For colorectal cancer, alternatives include oxaliplatin-based regimens (FOLFOX without the F), irinotecan-based regimens, targeted therapies (anti-EGFR or anti-VEGF antibodies), or immunotherapy for MSI-high tumors. For breast cancer, alternatives include anthracyclines, taxanes, and targeted therapies (trastuzumab, pertuzumab, CDK4/6 inhibitors). Your oncologist will design a treatment plan that avoids fluoropyrimidines while maintaining efficacy for your specific cancer type and stage.

Complete DPD deficiency can also cause symptoms unrelated to chemotherapy. Some homozygous individuals develop neurological symptoms (developmental delay, seizures) or gastrointestinal issues due to accumulation of endogenous pyrimidine metabolites. If you have unexplained neurological or GI symptoms, discuss with a geneticist or metabolic specialist.

TT Poor Metabolizer Absent

Complete DPD deficiency — fluoropyrimidines are contraindicated and potentially fatal

With two non-functional DPYD*2A alleles, you produce no active DPD enzyme. Studies of homozygous *2A patients show undetectable enzyme activity and inability to convert 5-FU to inactive metabolites. Without metabolism, fluoropyrimidines accumulate to lethal concentrations, causing rapid-onset pancytopenia (complete bone marrow shutdown), severe mucositis throughout the GI tract, and multi-organ toxicity. Multiple case reports document fatalities in homozygous DPYD*2A patients who received even fractions of standard fluoropyrimidine doses.

The FDA drug label explicitly states: "No dose of fluorouracil has been proven safe in individuals with absent DPD activity." There are case reports of attempted ultra-low-dose regimens (5-10% of standard) in compound heterozygotes with near-complete deficiency, but these remain experimental and carry high risk. The established standard of care is to avoid fluoropyrimidines entirely and select alternative chemotherapy regimens.

For colorectal cancer, alternatives include oxaliplatin-based regimens (FOLFOX without the F), irinotecan-based regimens, targeted therapies (anti-EGFR or anti-VEGF antibodies), or immunotherapy for MSI-high tumors. For breast cancer, alternatives include anthracyclines, taxanes, and targeted therapies (trastuzumab, pertuzumab, CDK4/6 inhibitors). Your oncologist will design a treatment plan that avoids fluoropyrimidines while maintaining efficacy for your specific cancer type and stage.

Complete DPD deficiency can also cause symptoms unrelated to chemotherapy. Some homozygous individuals develop neurological symptoms (developmental delay, seizures) or gastrointestinal issues due to accumulation of endogenous pyrimidine metabolites. If you have unexplained neurological or GI symptoms, discuss with a geneticist or metabolic specialist.