VCV000635263.14 - ClinVar

NM_000110.4(DPYD):c.1129-5923C>G

Germline

Top reviewed classifications are shown here.

Submission summary:

5 submissions

3 submitters

5 conditions

Reviewed by expert panel

Drug response

Oct 2022 by PharmGKB

for fluorouracil response - Other

Drug response

Oct 2022 by PharmGKB

for capecitabine response - Toxicity

Drug response

Oct 2022 by PharmGKB

for fluorouracil response - Toxicity

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000110.4(DPYD):c.1129-5923C>G

Variation ID: 635263 Accession: VCV000635263.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p21.3 1: 97579893 (GRCh38) [ NCBI UCSC ] 1: 98045449 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 1, 2019	Oct 20, 2024	Oct 27, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000110.4:c.1129-5923C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_000110.3:c.1129-5923C>G
NC_000001.11:g.97579893G>C
NC_000001.10:g.98045449G>C
NG_008807.2:g.346167C>G
LRG_722:g.346167C>G
LRG_722t1:c.1129-5923C>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:97579892:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00958 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00812

1000 Genomes Project 0.00958

Trans-Omics for Precision Medicine (TOPMed) 0.01198

The Genome Aggregation Database (gnomAD) 0.01296

Links

Genetic Testing Registry (GTR): GTR000569522 Genetic Testing Registry (GTR): GTR000613302 Genetic Testing Registry (GTR): GTR000613316 Genetic Testing Registry (GTR): GTR000613417 dbSNP: rs75017182 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DPYD		-	-	GRCh38 GRCh37	413	547

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
capecitabine response - Toxicity	drug response (1)	reviewed by expert panel	Oct 27, 2022	RCV001788348.11
fluorouracil response - Toxicity	drug response (1)	reviewed by expert panel	Oct 27, 2022	RCV001788349.11
fluorouracil response - Other	drug response (1)	reviewed by expert panel	Oct 27, 2022	RCV001788347.10
not provided	Benign (1)	criteria provided, single submitter	Jun 1, 2024	RCV003411727.10
DPYD-related disorder	Likely benign (1)	no assertion criteria provided	Jul 12, 2021	RCV003975320.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
drug response (Oct 27, 2022)	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine) Method: curation	fluorouracil response - Other Affected status: yes Allele origin: germline	PharmGKB Accession: SCV002031216.2 First in ClinVar: Dec 12, 2021 Last updated: Nov 04, 2023	Publications: PubMed (4) PubMed: 25410891‚ 27544765‚ 28295243‚ 31745289 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153906 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1451289700 Comment: PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more) PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C93, HLA-B57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
drug response Drug-variant association: Toxicity (Oct 27, 2022)	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine) Method: curation	capecitabine response - Toxicity Drug used for Neoplasms Affected status: yes Allele origin: germline	PharmGKB Accession: SCV002031215.2 First in ClinVar: Dec 12, 2021 Last updated: Nov 04, 2023 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (6) PubMed: 23736036‚ 24167597‚ 24923815‚ 25782327‚ 28427087‚ 29065426 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153906 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1451274165 Comment: PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more) PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C93, HLA-B57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
drug response Drug-variant association: Toxicity (Oct 27, 2022)	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine) Method: curation	fluorouracil response - Toxicity Drug used for Neoplasms Affected status: yes Allele origin: germline	PharmGKB Accession: SCV000925355.3 First in ClinVar: Jul 01, 2019 Last updated: Nov 04, 2023 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (9) PubMed: 20803296‚ 23736036‚ 24167597‚ 24923815‚ 26658227‚ 26794347‚ 28427087‚ 28614820‚ 29065426 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166153906 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1184986174 Comment: PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more) PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C93, HLA-B57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
Benign (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004124098.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: DPYD: BS1, BS2 Number of individuals with the variant: 21
Likely benign (Jul 12, 2021)	no assertion criteria provided Method: clinical testing	DPYD-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004789040.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

Comment:

Germline Functional Evidence

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines.	Lunenburg CATC	European journal of human genetics : EJHG	2020	PMID: 31745289
Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients.	Ruzzo A	British journal of cancer	2017	PMID: 29065426
Fluoropyrimidine-Associated Toxicity in Two Gastrointestinal Cancer Patients: Potential Role of Common DPYD Polymorphisms.	Falvella FS	Chemotherapy	2017	PMID: 28614820
Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity.	Meulendijks D	British journal of cancer	2017	PMID: 28427087
Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity.	Nie Q	Clinical pharmacology and therapeutics	2017	PMID: 28295243
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
DPYD Genotyping to Predict Adverse Events Following Treatment With Fluorouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer: A Secondary Analysis of the PETACC-8 Randomized Clinical Trial.	Boige V	JAMA oncology	2016	PMID: 26794347
Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).	Lee AM	Pharmacogenetics and genomics	2016	PMID: 26658227
DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.	Falvella FS	British journal of clinical pharmacology	2015	PMID: 25782327
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
Predicting 5-fluorouracil toxicity: DPD genotype and 5,6-dihydrouracil:uracil ratio.	Sistonen J	Pharmacogenomics	2014	PMID: 25410891
Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines.	Jennings BA	PloS one	2013	PMID: 24167597
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
Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity.	van Kuilenburg AB	Human genetics	2010	PMID: 20803296
https://www.pharmgkb.org/clinicalAnnotation/1184986174	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1451274165	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1451289700	-	-	-	-
https://www.pharmgkb.org/variant/PA166153906	-	-	-	-
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Text-mined citations for rs75017182 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000110.4(DPYD):c.1129-5923C>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs75017182 ...