DPYD M166V - GET-Evidence



(DPYD Met166Val)

Short summary

Associated with DPYD deficiency and poor prognosis for chemotherapy w/ 5-flurorouracil.

Variant evidence
Computational -
Functional -
Case/Control 5

This variant was identified as one of several variants in two of four cases of poor response to 5-flurorouracil by Gross et al. If this variant was the causative variant OR would be >5, however, Johnson et al conclude this variant is benign as it has no biochemical effect on DPYD levels and does not segregate with disease.

See Gross E et al. 2008 (19104657).

Familial -
Clinical importance
Severity 3

In severe cases, toxic reactions can lead to neuro and cardiac toxicity, and caused deaths in the study cohort.

See Gross E et al. 2008 (19104657).

Treatability 4

Other chemotherapy options may not be available, leading to an untreatable cancer, but there are alternative and/or reductions in dosage that may improve outcome.

See Gross E et al. 2008 (19104657).

Penetrance 5

“In the studied patient cohort, the attributable risk to suffer from severe drug-adverse effects due to the 496G-allele was 56.9%”

See Gross E et al. 2008 (19104657).



High clinical importance, Likely pharmacogenetic

(The "high clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


Total cases/controls case+ case– control+ control– p-value odds ratio
Hereditary Thymine-Uraciluria
22 7 70 82 0.0041 3.682


Allele frequency

  • C @ chr1:98165091: 7.8% (838/10758) in EVS
  • C @ chr1:97937678: 7.0% (9/128) in GET-Evidence
  • Frequency shown in summary reports: 7.8% (838/10758)


Johnson MR, Wang K, Diasio RB. Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype. Clin Cancer Res. 2002 Mar;8(3):768-74. PubMed PMID: 11895907.


show discussion


This is a small study with little value, considering the later study by Gross.

Gross E, Ullrich T, Seck K, Mueller V, de Wit M, von Schilling C, Meindl A, Schmitt M, Kiechle M. Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5-fluorouracil-related side effects. Hum Mutat. 2003 Dec;22(6):498. PubMed PMID: 14635116.

Found in two of four cancer patients (along with other mutations). Individuals were treated with a chemotherapy agent, 5-fluorouracil, and experienced side-effects. Control samples of 157 healthy individuals of Caucasian origin were randomly selected by Roche
Diagnostics, Penzberg. 7.9% of controls had the variant.

Gross E, Busse B, Riemenschneider M, Neubauer S, Seck K, Klein HG, Kiechle M, Lordick F, Meindl A. Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS One. 2008;3(12):e4003. Epub 2008 Dec 23. PubMed PMID: 19104657; PubMed Central PMCID: PMC2602733.


show discussion


I had to do some reverse-engineering of the case/control numbers from their data, since they reported bass-ackwards (% of cohort with each allele that had mild vs severe outcomes…)

Cases/controls case+ case– control+ control– p-value odds ratio
Hereditary Thymine-Uraciluria
22 7 70 82 0.0041 3.682



hu0D879F - CGI sample GS00253-DNA_G01_200_37
het C @ chr1:98165091






GS10851 - var-GS10851-1100-36-ASM
het C @ chr1:97937679


GS19026 - var-GS19026-1100-36-ASM
het C @ chr1:97937679


GS19669 - var-GS19669-1100-36-ASM
het C @ chr1:97937679


GS19700 - var-GS19700-1100-36-ASM
het C @ chr1:97937679


GS19834 - var-GS19834-1100-36-ASM
het C @ chr1:97937679


GS20502 - var-GS20502-1100-36-ASM
hom C @ chr1:97937679


Other external references

  • rs2297595
  • [capecitabine; fluorouracil]
    The DPYD:496A>G variant was associated with toxicity of fluoropyrimidine-based chemotherapy in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies.
  • Score: 0.998 (probably damaging)
    Web search results (30 hits -- see all)
  • Detailed Analysis of Five Mutations in Dihydropyrimidine ...
    of the highly conserved mutation sites M166V and S534N was additionally found in one of ... of missense mutations in the DPYD gene was shown to directly ...
  • Mutational analysis of the dihydropyrimidine dehydrogenase ...
    Mutational analysis of the dihydropyrimidine dehydrogenase [DPYD] gene in 125 patients treated with fluoropyrimidine-containing regimens. - ASCO - The American ...
  • Profound dihydropyrimidine dehydrogenase deficiency resulting ...
    Profound dihydropyrimidine dehydrogenase deficiency resulting from a ... in a C29R substitution (DPYD*9A) and A496G (M166V) in a family member with normal DPD enzyme activity] ...
  • Hypermethylation of the DPYD promoter region is not a major ...
    Recently, hypermethylation of the DPYD promoter region has been ... No evidence of DPYD promoter methylation was observed in any of the investigated ...
  • Pharmacogenetic and clinical aspects of dihydropyrimidine ...
    Alert me when this article is cited. Alert me if a correction is ... mutations have been identified in DPYD, including one splice-site mutation ...
  • Zhiling Yu, PhD* John T. Mondick, PhD Elke H. Krekels, MSc ...
    DPYD*9A: T85C. C29R. A496G. M166V. DPYD*5A: A1627G. I543V. DPYD*6: G2194A ... DPYD-g. enotype. Primary endpoint: Onset of toxicity independent of WHO grade. Trial ...
  • Gen-T 2, International Edition
    AT THE FO R E FRON T IN G EN OM IC M EDICIN E A N D R E S E ARCH WE'RE LEA DERS ... EuroEspes Building, 2nd Floor, Santa Marta de Babío s/n 15165 Bergondo, Coruña, ...
  • PP03_programme-abstr..>
    Published by: Drukkerij Peters in alliance with VU University Medical ... M.: Transcriptional regulation of DPYD gene expression and. aberrant methylation ...
  • Voordrachten
    Methods: DPYD, the gene encoding DPD, was ana- lyzed of pediatric patients with a ... (M166V, V335L, I560S and D949V) and 5 polymor- phisms (C29R, R21Q, ...
  • Table 1
    Clinical data of investigated patients, DPYD genotype and number of clones ... c.85T>C, C29R (H); c.496A>G, M166V; c.1236G>A, E412E c.1627A>G, I543V ...

Other in silico analyses

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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