MTR D919G - GET-Evidence

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MTR D919G

(MTR Asp919Gly)


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Short summary

This variant was weakly associated with a protective effect vs. colorectal cancer, but only in individuals with low alcohol consumption.

Variant evidence
Computational 2

PolyPhen: Benign score 0.183
SIFT: Tolerated 0.12
GVGD: GV 0.00; GD 93.77; Class C65
Mutation Tasting Prediction: Polymorphism, P value: 0.684308; no protein features affected.

Functional -
Case/Control 2

p = 0.04

See Ma J et al. 1999 (10498402).

Familial -
 
Clinical importance
Severity 4

colorectal cancer

Treatability 3

screening can reduce mortality by catching things early

Penetrance 1

~0.5% decreased risk

See Ma J et al. 1999 (10498402).

 

Impact

Low clinical importance, Uncertain protective

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

Inheritance pattern

other

Summary of published research, and additional commentary

 

Allele frequency

  • G @ chr1:237048500: 21.7% (2337/10758) in EVS
  • G @ chr1:235115122: 16.4% (21/128) in GET-Evidence
  • Frequency shown in summary reports: 21.7% (2337/10758)

Publications
 

Ma J, Stampfer MJ, Christensen B, Giovannucci E, Hunter DJ, Chen J, Willett WC, Selhub J, Hennekens CH, Gravel R, Rozen R. A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 1999 Sep;8(9):825-9. PubMed PMID: 10498402.

This study examined the frequency of this variant among cases of colorectal cancer vs. controls and found no significant difference. When individuals were split according to alcohol consumption (<1 drink/day vs. >= 1 drink/day) the variant had a weakly protective effect in individuals with low alcohol consumption, p=0.04.

If 2% of deaths are attributable to colorectal cancer, we estimate that based on these numbers that carriers with low alcohol consumption have ~0.5% attributable decreased risk for each copy of the variant.

Goode EL, Potter JD, Bigler J, Ulrich CM. Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev. 2004 Jan;13(1):157-62. PubMed PMID: 14744749.

protective from colorectal cancer
show discussion

Discussion

 

Kempisty B, Sikora J, Lianeri M, Szczepankiewicz A, Czerski P, Hauser J, Jagodzinski PP. MTHFD 1958G>A and MTR 2756A>G polymorphisms are associated with bipolar disorder and schizophrenia. Psychiatr Genet. 2007 Jun;17(3):177-81. PubMed PMID: 17417062.

 

Linnebank M, Malessa S, Moskau S, Semmler A, Pels H, Klockgether T, Schlegel U. Acute methotrexate-induced encephalopathy--causal relation to homozygous allelic state for MTR c.2756A>G (D919G)? J Chemother. 2007 Aug;19(4):455-7. PubMed PMID: 17855192.

 

Genomes
 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het G @ chr1:237048500

 

hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
het G @ chr1:237048500

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het G @ chr1:237048500

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het G @ chr1:237048500

 

 

 

 

Added in this revision:

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het G @ chr1:237048500

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het G @ chr1:237048500

 

 

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het G @ chr1:237048500

 

huD37D14 - CGI sample GS01175-DNA_A04 from PGP sample 13272228
het G @ chr1:237048500

 

GS18502 - var-GS18502-1100-36-ASM
het G @ chr1:235115123

 

GS18505 - var-GS18505-1100-36-ASM
het G @ chr1:235115123

 

GS18508 - var-GS18508-1100-36-ASM
het G @ chr1:235115123

 

GS18517 - var-GS18517-1100-36-ASM
het G @ chr1:235115123

 

GS18956 - var-GS18956-1100-36-ASM
het G @ chr1:235115123

 

GS19017 - var-GS19017-1100-36-ASM
het G @ chr1:235115123

 

GS19025 - var-GS19025-1100-36-ASM
het G @ chr1:235115123

 

GS19026 - var-GS19026-1100-36-ASM
hom G @ chr1:235115123

 

GS19129 - var-GS19129-1100-36-ASM
het G @ chr1:235115123

 

GS19648 - var-GS19648-1100-36-ASM
het G @ chr1:235115123

 

GS19649 - var-GS19649-1100-36-ASM
het G @ chr1:235115123

 

GS19704 - var-GS19704-1100-36-ASM
het G @ chr1:235115123

 

Other external references
 

    dbSNP
  • rs1805087
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [Colorectal Neoplasms]
    [ethanol]
    Risk or phenotype-associated allele: G Phenotype: The GG (Gly/Gly) genotype was associated with lower risk for colorectal cancer. This risk was further lowered in men with low alcohol intake. Study size: Study population/ethnicity: Patients with colorectal cancer from the Physicians' Health Study (PHS) and the Health Professional Follow-up Study (HPFS). Significance metric(s): OR = 0.59 (95% CI, 0.27-1.27); OR = 0.27 (95% CI, 0.09-0.81)(interaction with alcohol) Type of association: CO
    www.ncbi.nlm.nih.gov/pubmed/10498402
    PolyPhen-2
  • Score: 0.777 (possibly damaging)
    Web search results (242 hits -- see all)
  • Folate-related genes and the risk of tobacco-related cancers ...
    When stratified the genotype frequencies of MTR D919G by country, the departure from Hardy–Weinberg ... MTHFR C677T, A1298C and MTR D919G variants overall and stratified by ...
    carcin.oxfordjournals.org/cgi/content/full/28/6/1334
  • WikiGenes - MTR - 5-methyltetrahydrofolate-homocysteine...
    The world's first wiki where authorship really matters. Due credit and reputation for ... Neither MTR D919G nor RFC 80G>A polymorphisms were associated with altered colon ...
    www.wikigenes.org/e/gene/e/4548.html
  • The Methionine Synthase Polymorphism c.2756A>G Alters ...
    ferase (MTR; also called methionine synthase) catalyzes the ... MTR c.2756A>G (D919G) has been reported to reduce the. susceptibility to a number of other ...
    dach-liga-homocystein.org/Fachlit/publikationen/semmler2.pdf
  • Carcinogenesis -- Hung et al. 28 (6): 1334 Table BL2
    Table II. Effect of MTHFR C677T, A1298C and MTR D919G variants overall and stratified by age of onset ... MTR D919Ga. Overall. D/D. 887. 1089. 1. Reference. 277. 1089. 1. Reference. D/G ...
    carcin.oxfordjournals.org/cgi/content-nw/full/28/6/1334/TBL2
  • Polymorphisms in the reduced folate carrier, thymidylate ...
    Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase ... Neither MTR D919G nor RFC 80G>A polymorphisms were associated with altered colon ...
    tripdatabase.com/doc/369259-Polymorphisms-in-the-reduced-...
  • Analysis of methionine synthase reductase polymorphisms for ...
    MTR is an essential enzyme catalyzing the conversion of homocysteine to methionine. ... these polymorphisms and the D919G variant of MTR or the A222V variant ...
    www.ncbi.nlm.nih.gov/pubmed/15979034
  • DGNC2006 Wiss. Programm Poster P 06. P 06.77
    The c.2756A>G (D919G) polymorphism of the gene coding for 5-methyltetrahydrofolate ... Finally, MTR depends for its activity on 5-methyltetrahydrofolate as well as on ...
    www.dgnc.de/dgnc2006/index.php?nav=307&lan=d&print=ok
  • BioPortfolio - MTR
    The Mtr respiratory pathway is essential for reducing flavins and ... frequencies of MTHFD1 1958G >A (R653Q) and MTR 2756A>G (D919G) gene polymorphisms in a group of bipolar ...
    www.bioportfolio.com/search/MTR.html
  • The methionine synthase polymorphism c.2756A>G alters ...
    The methionine synthase polymorphism c.2756A>G alters susceptibility to glioblastoma ... methionine synthase (MTR) c.2756A>G (D919G) and methylenetetrahydrofolate reductase ...
    tripdatabase.com/doc/368862-The-methionine-synthase-polym...

Other in silico analyses
 

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

Edit history
 

Gene search

"GENE" or "GENE A123C":

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