Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 2 annotations for this variant. Register or sign in to see them.
VIP Variant in CYP2A6
The rs5031016 (g. 6558T>C, Ile471Thr) variant is found in the CYP2A6*7 , *10, *19, *36, *37 alleles as defined by the CYP-450 nomenclature committee: http://www.cypalleles.ki.se/cyp2a6.htm. See the PharmGKB CYP2A6 haplotype tab for more details.
Please note; several other variants and/ or a a gene conversion in the 3' flanking region also make up the CYP2A6*7 , *10, *19, *36, *37 alleles, as defined by the CYP-450 nomenclature committee: http://www.cypalleles.ki.se/cyp2a6.htm.
rs5031016 T>C is associated with reduced nicotine metabolism [Article:11237731].
The following pharmacogenetic studies genotyped for this variant:
| CYP2A6 Allele or Genotype | Details of genotyping | Drug | Association | Reference and study details |
|---|---|---|---|---|
| Genotype *1/*1 | Sequenced for *9 at -48T>G (rs28399433), *10 at 6600G>T (rs28399468), *7 at 6558T>C (rs5031016). *4 gene deletion. Therefore *1 was defined as wildtype with none of the above variants. | S-1 and oxaliplatin | Associated with increased tegafur metabolism and a trend for higher 5 FU plasma concentrations compared to individuals with one or two variant alleles (*4, *7, *9, *10 combined) (p values were not given), but not associated with increased likelihood of diarrhea or neutropenia. | [Article:21326246] Study: Biliary tract cancer patients, (n=48). |
| Allele *7 | g.6558T>C (Ile471Thr) (rs5031016) and gene conversion with CYP2A7 in the 3' UTR | Tegafur | Reduced 5 FU formation rate compared to *1A/*1A | [Article:15900015] In vitro kinetic assays, using transformed E. coli membrane preparations (n=3) |
| Allele *19 | g.5668A>T (Tyr392Phe) (rs1809810) and g.6354T>C (intron 8), 6558T>C (Ile471Thr) (rs5031016) and gene conversion with CYP2A7 in the 3' UTR. Allele specific primers used for genotyping. | Tegafur | Reduced 5 FU formation rate compared to *1A/*1A | [Article:15900015] In vitro kinetic assays, using transformed E. coli membrane preparations (n=3) |
| Individuals with two variant alleles (*4/*4, *7/*7 or *4/*7) | *7: c.1412T>C, Ile471Thr (rs5031016) | S-1 | Significantly reduced oral clearance of tegafur, compared to *1/*1 | [Article:18380793] n=54 Japanese patients |
| Individuals with two variant alleles, (combined genotypes): *4/*4,*4/*7,*4/*9,*7/*9,*9/*9 | Alleles defined by: *4: entire gene deletion, positions genotyped: g.-48T>G (for *9) (rs28399433), g. 6558T>C (rs5031016 Ile471Thr) (for *7, *10), and g. 6600G>T (rs28399468, Arg485Leu ) (for *10) | S-1 | Reduced treatment efficacy compared to individuals with one or two wildtype *1 alleles. Increased risk of disease progression and reduced progression-free survival, as measured by significantly reduced probability of tumor response | [Article:19604090] n= 50 Korean patients with metastatic gastric cancer |
| Two variant alleles, (combined genotypes): *4A/*4A,*4A/*7,*4A/*9,*7/*7,*7/*9,*9/*9 | (introduction describes *7 as c.1412T>C (rs5031016 Ile471Thr), and *9 as g.-48T>G (rs28399433), and *4 as complete lack of activity.) | S-1 | Associated with significantly reduced tegafur clearance, compared to *1/*1 or heterozygotes with one variant allele (tegafur plasma concentrations did not correlate with 5 FU concentrations) | [Article:20596643] n=57 Japanese patients with solid tumors. |
| Individuals with two variant alleles, (combined genotypes): *4A/*4A,*4A/*9,*4A/*10,*7/*9,*9/*9,*9/*10 | Alleles defined by: *4 gene deletion, *7: c.1412T>C , Ile471Thr (rs5031016), *9: g.-48T>G (rs28399433) | S-1 | Associated with higher tegafur and significantly lower 5 FU plasma concentrations compared to heterozygote patients (*1/*4A, *1/*7, *1/*9, *1/*11 combined genotypes). No significant association with adverse effects or treatment response were found. | [Article:19921195] n=34 patients with solid tumors. |
| Individuals with one or two variant alleles, (combined genotypes): *4/*7,*4/*9,*4/*10,*9/*9, *1/*4 | Alleles defined by: *4 entire gene deletion, positions genotyped: g.-48T>G (rs28399433) (for *9), g.6558T>C (rs5031016 Ile471Thr) (for *7, *10), and g.6600G>T (rs28399468, Arg485Leu ) (for *10). | S-1 and cisplatin | Significantly associated with lower response rate, increased risk of disease progression and reduced overall survival time. | [Article:21364592] n=106, Korean patients, with metastatic gastric cancer |
| Two loss-of-function alleles (*2, *4A-F, *5, *34) or two reduced function alleles (*1H, *1J, *7, *9, *10, *12, *13, *15, *17, *19) or one of each | *1X2A, *1X2B: gene duplication, *1H and *1J: rs61663607 g.-745A>G, *2: rs1801272 g.1799T>A, *4A, *4F: intron 8 gene conversion with CYP2A7 - gene deletion. *5: rs5031017 g.6582G>T, *7, *10, *19: rs5031016 g.6558T>C, *9, *13, *15: rs28399433 g.-48T>G, *17: rs28399454 g.5065G>A, *12: intron 2 gene conversion with CYP2A7, *34: intron 4, gene conversion with CYP2A7. | Efavirenz | Reduced EFV metabolism significantly higher EFV plasma AUC compared to those without variant alleles (in individuals with CYP2B6 reference alleles please note reference alleles were not stated in the study). | [Article:19238117] n=169 mixed population, HIV-infected individuals, The Swiss HIV Cohort Study. |
| Genotype *7/*9 or *4A/*7 or *4A/*9 or *4A/*10 | *4A (entire gene deletion), *7: Ile471Thr (rs5031016),*8: Arg485Leu (rs28399468), *9: g.-48T>G (rs28399433), *10: Ile471Thr (rs5031016) and Arg485Leu (rs28399468) | Pilocarpine | Poor metabolism and low clearance. | [Article:18698229] study 1 n=20, study 2 n=8, healthy Japanese individuals administered with a single dose of pilocarpine hydrochloride. |
The CYP2A6 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations and haplotypes will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
Publications related to rs5031016 at chr19:41349774: 2
| An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles. Biochemical and biophysical research communications. 2002. Xu C, et al. [Article:11779172@PubMed] | |
| Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. British journal of clinical pharmacology. 2002. Yoshida Ryoko, et al. [Article:12445030@PubMed] |
Cross-References
- UCSC Golden Path:
- chr19:41349774
- dbSNP:
- rs5031016
- JSNP:
- ssj0008578
- LS-SNP:
- rs5031016
Platform Availability
- Illumina