DTNBP1 P272S - GET-Evidence

Curation:
Currentness:

DTNBP1 P272S

(DTNBP1 Pro272Ser)


Short summary

Possibly a slight protective effect against colorectal cancer if homozygous.

Variant evidence
Computational

Polyphen 2 predicts “possibly damaging” effect

Functional -
Case/Control 2

Webb et al. report p=0.03 after multiple hypothesis adjustment, kin-cohort data had insufficient evidence to evaluate or contradict.

Familial

No familial data

 
Clinical importance
Severity 3

Colorectal cancer

Treatability 3

Screening

Penetrance 2

See below

See Webb EL et al. 2006 (17000706).

 

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

recessive

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr6:15523448: 3.5% (378/10758) in EVS
  • A @ chr6:15631426: 3.1% (4/128) in GET-Evidence
  • Frequency shown in summary reports: 3.5% (378/10758)

Publications
 

Webb EL, Rudd MF, Sellick GS, El Galta R, Bethke L, Wood W, Fletcher O, Penegar S, Withey L, Qureshi M, Johnson N, Tomlinson I, Gray R, Peto J, Houlston RS. Search for low penetrance alleles for colorectal cancer through a scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by kin-cohort analysis of 14 704 first-degree relatives. Hum Mol Genet. 2006 Nov 1;15(21):3263-71. Epub 2006 Sep 25. PubMed PMID: 17000706.

This variant is reported in a search for low penetrance Colorectal cancer alleles among a scan of 1,467 nonsynonymous polymorphisms. It seems to have a weakly-significant protective effect, with an odds ratio of 0.28 (0.09-0.84) and multiple-hypothesis-adjusted p-value of 0.03 for a recessive hypothesis. Kin-cohort data appears to have had insufficient observations to make any conclusions (confidence interval is extremely large: 0.00 – 12.63).

Based on the odds ratio of 0.28 (a protective effect), a recessive hypothesis, and minor allele frequency of 5% in controls (.25% homozygous), and a lifetime risk of 7% for colorectal cancer, we estimate this data suggests homozygotes for this variant have a 2-3% decreased risk. This number is likely to be higher than the true value (if any effect exists) due to publication bias.

Genomes
 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr6:15523448

 

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het A @ chr6:15523448

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het A @ chr6:15523448

 

 

GS10851 - var-GS10851-1100-36-ASM
het A @ chr6:15631427

 

Other external references
 

    dbSNP
  • rs17470454
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.818 (possibly damaging)
    Web search results (7 hits -- see all)
  • Molecular Psychiatry - Figures and tables for article: The ...
    Two nonsynonymous SNPs (rs16876589: G214D, rs17470454: P272S) in isoform a are indicated. Full figure and ... ( a) DTNBP1 interactome contains 31 proteins that directly interact ...
    www.nature.com/mp/journal/v14/n1/fig_tab/mp200888ft.html
  • Molecular Psychiatry - Figure 1 for article: The dystrobrevin ...
    Alignment of the 13 DTNBP1 amino acid sequences. The multiple ... nonsynonymous SNPs (rs16876589: G214D, rs17470454: P272S) in isoform a are indicated. ...
    www.nature.com/mp/journal/v14/n1/fig_tab/mp200888f1.html
  • Search for low penetrance alleles for colorectal cancer ...
    DTNBP1. P272S. 0.05. 0.03. R. 0.28. 0.09. 0.84. 11.33. 0.00. 12.63. rs1800076 ... P272S. Possibly damaging/intolerant. DTNBP1. Dystrobrevin binding protein 1. Muscle ...
    hmg.oxfordjournals.org/cgi/reprint/15/21/3263.pdf
  • Supplementary Table xls.1
    rs16876571*DTNBP1 NM_183040 NP_898861*H297Y*dystrobrevin binding protein 1 ... rs17470454 NM_032122 NP_115498*P272S NM_183041 NP_898862*P191S. rs17472401*R848W ...
    icr.ac.uk/research/research_sections/.../2843.xls
  • Hum. Mol. Genet. -- Webb et al. 15 (21): 3263 Figure DL401TB1
    DTNBP1. P272S. 0.05. 0.03. R. 0.28. 0.09. 0.84. 11.33. 0.00. 12.63. rs1800076 ... cMost significant association under a dominant (D) or recessive (R) model. ...
    hmg.oxfordjournals.org/cgi/content-nw/.../21/3263/DDL401TB1

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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