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NM_000110.4(DPYD):c.1601G>A (p.Ser534Asn)

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Interpretation:
Conflicting interpretations of pathogenicity​

Benign(3);Likely benign(2);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
9 (Most recent: Jul 4, 2021)
Last evaluated:
Mar 26, 2018
Accession:
VCV000100094.10
Variation ID:
100094
Description:
single nucleotide variant
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NM_000110.4(DPYD):c.1601G>A (p.Ser534Asn)

Allele ID
105971
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
1p21.3
Genomic location
1: 97515865 (GRCh38) GRCh38 UCSC
1: 97981421 (GRCh37) GRCh37 UCSC
1: 97754009 (NCBI36) NCBI36 UCSC
HGVS
Nucleotide Protein Molecular
consequence
Q12882:p.Ser534Asn
NC_000001.9:g.97754009C>T
NM_000110.3:c.1601G>A NP_000101.2:p.Ser534Asn missense
... more HGVS
Protein change
S534N
Other names
-
Canonical SPDI
NC_000001.11:97515864:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
0.00958 (T)

Allele frequency
The Genome Aggregation Database (gnomAD) 0.01144
The Genome Aggregation Database (gnomAD), exomes 0.01470
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01492
Trans-Omics for Precision Medicine (TOPMed) 0.01235
1000 Genomes Project 0.00958
Exome Aggregation Consortium (ExAC) 0.01416
Links
ClinGen: CA228124
UniProtKB: Q12882#VAR_005175
dbSNP: rs1801158
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Benign 2 criteria provided, multiple submitters, no conflicts Mar 29, 2016 RCV000249334.2
Conflicting interpretations of pathogenicity 4 criteria provided, conflicting interpretations Mar 26, 2018 RCV000086477.3
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Apr 27, 2017 RCV000603277.3
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
DPYD - - GRCh38
GRCh37
232 300

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Benign
(-)
criteria provided, single submitter
Method: clinical testing
NOT SPECIFIED
Allele origin: germline
PreventionGenetics,PreventionGenetics
Accession: SCV000302300.1
Submitted: (Apr 28, 2016)
Evidence details
Benign
(Aug 03, 2015)
criteria provided, single submitter
Method: clinical testing
Dihydropyrimidine dehydrogenase deficiency
Allele origin: germline
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743428.1
Submitted: (Apr 17, 2018)
Evidence details
Likely benign
(Sep 08, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Athena Diagnostics Inc
Accession: SCV000841878.1
Submitted: (Aug 31, 2018)
Evidence details
Publications
PubMed (56)
Benign
(Mar 29, 2016)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000331345.4
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Likely benign
(Mar 26, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000977480.1
Submitted: (Apr 12, 2019)
Evidence details
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
Uncertain significance
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Dihydropyrimidine dehydrogenase deficiency
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001256862.1
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (2)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Uncertain significance
(Jan 01, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV000574775.11
Submitted: (Jul 04, 2021)
Evidence details
Benign
(-)
no assertion criteria provided
Method: clinical testing
Dihydropyrimidine dehydrogenase deficiency
Allele origin: germline
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000734053.1
Submitted: (Apr 04, 2018)
Evidence details
not provided
(-)
no assertion provided
Method: not provided
not provided
Allele origin: unknown
Diasio Lab, Mayo Clinic
Accession: SCV000118643.1
Submitted: (Oct 27, 2009)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Use of exome sequencing to determine the full profile of genetic variants in the fluoropyrimidine pathway in colorectal cancer patients affected by severe toxicity. Pellicer M Pharmacogenomics 2017 PMID: 28745575
Adjuvant S-1 chemotherapy after curative resection of gastric cancer. Leung JS Hong Kong medical journal = Xianggang yi xue za zhi 2017 PMID: 28572524
Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity. Meulendijks D British journal of cancer 2017 PMID: 28427087
Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: Assessment of a multiparametric approach. Boisdron-Celle M Seminars in oncology 2017 PMID: 28395758
Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity. Nie Q Clinical pharmacology and therapeutics 2017 PMID: 28295243
Pharmacogenetics of anti-cancer drugs: State of the art and implementation - recommendations of the French National Network of Pharmacogenetics. Quaranta S Therapie 2017 PMID: 28262261
Pharmacogenetics-based personalized therapy: Levels of evidence and recommendations from the French Network of Pharmacogenetics (RNPGx). Picard N Therapie 2017 PMID: 28237406
Pharmacogenetics and Metabolism from Science to Implementation in Clinical Practice: The Example of Dihydropyrimidine Dehydrogenase. Del Re M Current pharmaceutical design 2017 PMID: 28128059
Relevance of dihydropyrimidine-dehydrogenase and thymidylate-synthase in patients with pancreatic neuroendocrine neoplasms treated with 5-FU-based chemotherapy. Krug S Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 2017 PMID: 28027897
Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing. van Kuilenburg AB Biochimica et biophysica acta. Molecular basis of disease 2017 PMID: 28024938
Recommendation on testing for dihydropyrimidine dehydrogenase deficiency in the ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Deenen MJ Annals of oncology : official journal of the European Society for Medical Oncology 2017 PMID: 27701067
Association of genetic variability in enzymes metabolizing chemotherapeutic agents with treatment response in head and neck cancer cases. Dhawan A Asia-Pacific journal of clinical oncology 2017 PMID: 26792652
Revisiting the morbid genome of Mendelian disorders. Abouelhoda M Genome biology 2016 PMID: 27884173
Patients homozygous for DPYD c.1129-5923C>G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines. Meulendijks D Cancer chemotherapy and pharmacology 2016 PMID: 27544765
Highlight on DPYD gene polymorphisms and treatment by capecitabine (.). Milano G Scandinavian journal of clinical and laboratory investigation. Supplementum 2016 PMID: 27454530
Cost-effectiveness of screening for DPYD polymorphisms to prevent neutropenia in cancer patients treated with fluoropyrimidines. Cortejoso L Pharmacogenomics 2016 PMID: 27248859
Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Campbell JM Pharmacogenomics 2016 PMID: 26894782
Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene. Kuilenburg ABPV Biochimica et biophysica acta 2016 PMID: 26804652
Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity. Meulendijks D International journal of cancer 2016 PMID: 26804235
Prospective DPYD genotyping to reduce the risk of fluoropyrimidine-induced severe toxicity: Ready for prime time. Lunenburg CATC European journal of cancer (Oxford, England : 1990) 2016 PMID: 26716401
Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes: A GeT-RM Collaborative Project. Pratt VM The Journal of molecular diagnostics : JMD 2016 PMID: 26621101
Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio. Thomas F Clinical pharmacology and therapeutics 2016 PMID: 26265035
Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Meulendijks D The Lancet. Oncology 2015 PMID: 26603945
Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score. Henricks LM Pharmacogenomics 2015 PMID: 26265346
Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity. Froehlich TK International journal of cancer 2015 PMID: 24923815
Dihydropyrimidine dehydrogenase 85T>C mutation is associated with ocular toxicity of 5-fluorouracil: a case report. Baskin Y American journal of therapeutics 2015 PMID: 24434920
Predicting 5-fluorouracil toxicity: DPD genotype and 5,6-dihydrouracil:uracil ratio. Sistonen J Pharmacogenomics 2014 PMID: 25410891
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. Tabor HK American journal of human genetics 2014 PMID: 25087612
Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. Offer SM Cancer research 2014 PMID: 24648345
Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Caudle KE Clinical pharmacology and therapeutics 2013 PMID: 23988873
Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Loganayagam A British journal of cancer 2013 PMID: 23736036
Phenotypic profiling of DPYD variations relevant to 5-fluorouracil sensitivity using real-time cellular analysis and in vitro measurement of enzyme activity. Offer SM Cancer research 2013 PMID: 23328581
Gender-specific elimination of continuous-infusional 5-fluorouracil in patients with gastrointestinal malignancies: results from a prospective population pharmacokinetic study. Mueller F Cancer chemotherapy and pharmacology 2013 PMID: 23139054
An informatics approach to analyzing the incidentalome. Berg JS Genetics in medicine : official journal of the American College of Medical Genetics 2013 PMID: 22995991
Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Deenen MJ Clinical cancer research : an official journal of the American Association for Cancer Research 2011 PMID: 21498394
Carrier testing for severe childhood recessive diseases by next-generation sequencing. Bell CJ Science translational medicine 2011 PMID: 21228398
Dihydropyrimidine dehydrogenase polymorphisms and fluoropyrimidine toxicity: ready for routine clinical application within personalized medicine? Del Re M The EPMA journal 2010 PMID: 23199091
A map of human genome variation from population-scale sequencing. 1000 Genomes Project Consortium. Nature 2010 PMID: 20981092
Routine dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil-related severe toxicities: hype or hope? Ciccolini J Clinical colorectal cancer 2010 PMID: 20920994
Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy. Kleibl Z Neoplasma 2009 PMID: 19473056
Cardiotoxicity of 5-fluorouracil and capecitabine in a pancreatic cancer patient with a novel mutation in the dihydropyrimidine dehydrogenase gene. Shahrokni A JOP : Journal of the pancreas 2009 PMID: 19287123
The dihydrouracil/uracil ratio in plasma, clinical and genetic analysis for screening of dihydropyrimidine dehydrogenase deficiency in colorectal cancer patients treated with 5-fluorouracil. Ben Fredj R Pathologie-biologie 2009 PMID: 18619742
Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. Gross E PloS one 2008 PMID: 19104657
Hypermethylation of the DPYD promoter region is not a major predictor of severe toxicity in 5-fluorouracil based chemotherapy. Amstutz U Journal of experimental & clinical cancer research : CR 2008 PMID: 18937829
Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in Chinese cancer patients. He YF Journal of clinical pharmacy and therapeutics 2008 PMID: 18452418
Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. Schwab M Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008 PMID: 18299612
Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis. Sellick GS Blood 2008 PMID: 18006695
Insights into the role of heritable genetic variation in the pharmacokinetics and pharmacodynamics of anticancer drugs. Pander J Expert opinion on pharmacotherapy 2007 PMID: 17563256
Identification of a novel mutation in the dihydropyrimidine dehydrogenase gene in a patient with a lethal outcome following 5-fluorouracil administration and the determination of its frequency in a population of 500 patients with colorectal carcinoma. Morel A Clinical biochemistry 2007 PMID: 17046731
Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals. Seck K Clinical cancer research : an official journal of the American Association for Cancer Research 2005 PMID: 16115930
Multiple organ failure due to 5-fluorouracil chemotherapy in a patient with a rare dihydropyrimidine dehydrogenase gene variant. Lazar A Onkologie 2004 PMID: 15591715
Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5-fluorouracil-related side effects. Gross E Human mutation 2003 PMID: 14635116
High prevalence of the IVS14 + 1G>A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Van Kuilenburg AB Pharmacogenetics 2002 PMID: 12360106
A comparative analysis of translated dihydropyrimidine dehydrogenase cDNA; conservation of functional domains and relevance to genetic polymorphisms. Mattison LK Pharmacogenetics 2002 PMID: 11875367
Known variant DPYD alleles do not explain DPD deficiency in cancer patients. Collie-Duguid ES Pharmacogenetics 2000 PMID: 10803677
Inherited variations in drug-metabolizing enzymes: significance in clinical oncology. Iyer L Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology 1999 PMID: 10671643
Characterization of the human dihydropyrimidine dehydrogenase gene. Wei X Genomics 1998 PMID: 9721209
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DPYD - - - -

Text-mined citations for rs1801158...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 07, 2021