Mutation analysis: DPD for 5-fluorouracil toxicity
Description:
Polymorphic variants in the DPYD gene are associated with severe, sometimes fatal, toxicity to fluoropyrimidine therapy. The Purine Research Laboratory in Biochemical Sciences offers a DPYD panel of five variants as a diagnostic test to predict fluoropyrimidine toxicity.
Clinical details:
The fluoropyrimidine drugs capecitabine and 5-fluorouracil are widely used for the treatment of solid tumours, including colorectal and metastatic breast cancers. Pharmacogenetic variation in the DPYD gene is associated with early, severe toxicity to fluoropyrimidine therapy. Testing should be done prior to the start of therapy and the starting dose adjusted according to DPYD genotype.
Report comments for wild-type and heterozygous variant DPYD genotypes (2):
1. No variants = wild-type (normal metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
No DPYD variants were found. DPD deficiency is unlikely to be a cause of severe toxicity to fluoropyrimidine therapy. However, the presence of a rare variant which could cause toxicity cannot be excluded.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
2. Heterozygous DPYD c.1905+1G>A (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is heterozygous for the variant DPYD c.1905+1G>A. A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, titrate dose increases based on toxicity or therapeutic drug monitoring over subsequent cycles to a maximum of 75% of target dose.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
3. Heterozygous c.1679T>G, p.(Ile560Ser) (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is heterozygous for the variant DPYD c.1679T>G p.(Ile560Ser). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, titrate dose increases based on toxicity or therapeutic drug monitoring over subsequent cycles to a maximum of 75% of target dose.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
4. Heterozygous c.2846A>T p.(Asp949Val) (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.2846A>T p.(Asp949Val). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
5. Heterozygous c.1129-5923C>G/HapB3 (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.1129-5923C>G/HapB3. A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
6. Heterozygous c.557A>G, p.(Tyr186Cys)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.557A>G p.(Tyr186Cys). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
Examples of report comments for homozygous and compound heterozygous genotypes
1. Compound heterozygous c.2846A>T / c.1905+1G>A (poor metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1905+1G>A and c.2846A>T p.(Asp949Val).
Avoid use of fluoropyrimidine therapy. Consider raltitrexed or trifluridine/tipiracil or alternate therapy.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: This assay cannot assess variant phasing. Interpretation of this result assumes that the two reported variants are present on different alleles (in trans).
2. Homozygous c.1905+1G>A/ c.1905+1G>A (poor metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c.1905+1G>A. A homozygous genotype is associated with complete DPD deficiency and extremely severe, usually fatal toxicity to fluoropyrimidine therapy.
Do not use fluoropyrimidine therapy. Consider raltitrexed or trifluridine/tipiracil.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The variant appears homozygous; however, a deletion of the second allele cannot be excluded.
3. Homozygous c.2846A>T/c.2846A>T (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c. c.2846A>T, p.(Asp949Val).
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, titrate dose increases against toxicity or therapeutic drug monitoring over subsequent cycles to a maximum of 75% of the target dose.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The variant appears homozygous; however, a deletion of the second allele cannot be excluded.
4. Compound heterozygous c.2846A>T/c.1129-5923C>G (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1129-5923C>G/HapB3 and c.2846A>T p.(Asp949Val).
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, titrate dose increases against toxicity or therapeutic drug monitoring over subsequent cycles to a maximum of 75% of the target dose.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: This assay cannot assess variant phasing. Interpretation of this result assumes that the two reported variants are present on different alleles (in trans
Report comments for wild-type and heterozygous variant DPYD genotypes (2):
1. No variants = wild-type (normal metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
No DPYD variants were found. DPD deficiency is unlikely to be a cause of severe toxicity to fluoropyrimidine therapy. However, the presence of a rare variant which could cause toxicity cannot be excluded.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
2. Heterozygous DPYD c.1905+1G>A (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is heterozygous for the variant DPYD c.1905+1G>A. A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, titrate dose increases based on toxicity or therapeutic drug monitoring over subsequent cycles to a maximum of 75% of target dose.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
3. Heterozygous c.1679T>G, p.(Ile560Ser) (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is heterozygous for the variant DPYD c.1679T>G p.(Ile560Ser). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, titrate dose increases based on toxicity or therapeutic drug monitoring over subsequent cycles to a maximum of 75% of target dose.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
4. Heterozygous c.2846A>T p.(Asp949Val) (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.2846A>T p.(Asp949Val). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
5. Heterozygous c.1129-5923C>G/HapB3 (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.1129-5923C>G/HapB3. A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
6. Heterozygous c.557A>G, p.(Tyr186Cys)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
The patient is heterozygous for the variant DPYD c.557A>G p.(Tyr186Cys). A heterozygous genotype is associated with partial DPD deficiency and severe toxicity to fluoropyrimidine therapy at standard doses.
Consider a 50% dose reduction. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, but caution is advised.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G (HapB3), c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The presence of a rare DPYD variant not detected by this assay which may contribute to fluoropyrimidine toxicity, cannot be excluded.
Examples of report comments for homozygous and compound heterozygous genotypes
1. Compound heterozygous c.2846A>T / c.1905+1G>A (poor metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1905+1G>A and c.2846A>T p.(Asp949Val).
Avoid use of fluoropyrimidine therapy. Consider raltitrexed or trifluridine/tipiracil or alternate therapy.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach For Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: This assay cannot assess variant phasing. Interpretation of this result assumes that the two reported variants are present on different alleles (in trans).
2. Homozygous c.1905+1G>A/ c.1905+1G>A (poor metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c.1905+1G>A. A homozygous genotype is associated with complete DPD deficiency and extremely severe, usually fatal toxicity to fluoropyrimidine therapy.
Do not use fluoropyrimidine therapy. Consider raltitrexed or trifluridine/tipiracil.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The variant appears homozygous; however, a deletion of the second allele cannot be excluded.
3. Homozygous c.2846A>T/c.2846A>T (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is homozygous for the variant DPYD c. c.2846A>T, p.(Asp949Val).
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, titrate dose increases against toxicity or therapeutic drug monitoring over subsequent cycles to a maximum of 75% of the target dose.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: The variant appears homozygous; however, a deletion of the second allele cannot be excluded.
4. Compound heterozygous c.2846A>T/c.1129-5923C>G (intermediate metaboliser)
DPYD VARIANT ANALYSIS – FLUOROPYRIMIDINE TOXICITY
CAUTION: HIGH RISK OF FATAL TOXICITY. The patient is compound heterozygous for the variants DPYD c.1129-5923C>G/HapB3 and c.2846A>T p.(Asp949Val).
Consider a 50% dose reduction or alternative therapy. If tolerant after the first cycle, titrate dose increases against toxicity or therapeutic drug monitoring over subsequent cycles to a maximum of 75% of the target dose.
The patient was genotyped for the DPYD variants c.557A>G p.(Tyr186Cys), c.1129-5923C>G/HapB3, c.1679T>G p.(Ile560Ser), c.1905+1G>A, c.2846A>T p.(Asp949Val) by TaqMan genotyping assays. Reference sequence NM_000110.4. Dosing guidance reference: UK Chemotherapy Board Personalised Medicine Approach for Fluoropyrimidine-based Therapies (v2 September 2024).
Assay limitation: This assay cannot assess variant phasing. Interpretation of this result assumes that the two reported variants are present on different alleles (in trans
Department:
Location:
Sample type and Volume required:
3 mL blood EDTA (purple top)
Turnaround time:
3 days
Storage and transport:
Store in fridge, (don’t freeze) to lab within 5 days/1st class post
Contacts:
Inherited Metabolic Diseases Unit at Blackfriars Hub
07592 502653
Reference Chemistry, 1st Floor Blackfriars Hub
Friars Bridge Court
Blackfriars Road
London
SE1 8NZ
Friars Bridge Court
Blackfriars Road
London
SE1 8NZ
Laboratory:
Last updated: 19/01/2026
