RNASEL E265X - GET-Evidence



(RNASEL Glu265Stop)

You are viewing the latest version of this page, saved on November 13, 2012 at 12:58pm by Madeleine Ball.

Short summary

Implicated in causing familial prostate cancer, but later findings fail to confirm this. The variant is equally common in the control population, which strongly contradicts the original hypothesis of a high penetrance effect. If the variant has any effect on prostate cancer it seems likely to be low penetrance (any evidence for this is, however, very weak).

Variant evidence
Computational 2

Variant predicted to be highly disruptive

Functional 1

Functional studies find this variant has lost enzyme activity

See Carpten J et al. 2002 (11799394).

Case/Control -1

No enrichment found in cases vs. controls, contradicting the high penetrance effect proposed by Carpten et al.

See Carpten J et al. 2002 (11799394), Maier C et al. 2005 (15714208).

Familial -
Clinical importance
Severity 3
Treatability 4
Penetrance 2


Low clinical importance, Uncertain pathogenic

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

Inheritance pattern


Summary of published research, and additional commentary


Total cases/controls case+ case– control+ control– p-value odds ratio
Prostate cancer
4 617 6 531 0.5275 0.574


Allele frequency

  • A @ chr1:182555149: 0.3% (31/10758) in EVS
  • Frequency shown in summary reports: 0.3% (31/10758)


Edited in this revision:

Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E, Hu P, Bujnovszky P, Makalowska I, Baffoe-Bonnie A, Faith D, Smith J, Stephan D, Wiley K, Brownstein M, Gildea D, Kelly B, Jenkins R, Hostetter G, Matikainen M, Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De Marzo A, Papadopoulos N, Kallioniemi OP, Burk R, Meyers D, Grönberg H, Meltzer P, Silverman R, Bailey-Wilson J, Walsh P, Isaacs W, Trent J. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet. 2002 Feb;30(2):181-4. Epub 2002 Jan 22. PubMed PMID: 11799394.

This report implicates variants in RNASEL, including this variant, in causing hereditary prostate cancer type I. The study describes combining data from 91 families to perform linkage analysis — results implicated several prostate susceptibility loci, including this one. (No statistical significance is given, the authors write it “suggests HPC1 maps to [this region]”.)

This variant was seen in one of 26 families, 8 of which were selected on the basis of apparent linkage and shared haplotypes in this region. The variant segregates with disease in the four brothers studied, but this is expected as the family was selected for sequencing on the basis of shared haplotypes.

Unaffected white males, unrelated CEPH samples (HapMap), and US population controls had this variant heterozygously in 3 individuals out of 330 (3 out of 660 alleles). They also studied 258 sporadic (non-hereditary) prostate cancer cases and found the variant heterozygously in two individuals. This seems to contradict a pathogenic hypothesis; the authors comment “as yet we cannot identify a difference in allele frequency between affected individuals and controls.”

Functional analysis of the variant found that cell lines carrying this variant heterozygously have half the RNAse L enzyme activity compared to wild-type cells.

Cases/controls case+ case– control+ control– p-value odds ratio
Prostate cancer
2 256 3 327 1.0000 0.852


Maier C, Haeusler J, Herkommer K, Vesovic Z, Hoegel J, Vogel W, Paiss T. Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene. Br J Cancer. 2005 Mar 28;92(6):1159-64. PubMed PMID: 15714208; PubMed Central PMCID: PMC2361943.

These authors conclude that their results are not consistent with a high penetrance effect of RNASEL variants in causing prostate cancer.

They screen 136 familial cases, 227 sporadic cases, and 207 controls. This variant was seen in 1 familial case, 1 sporadic case, and 3 control cases. This failure to find any enrichment in familial cases strongly contradicts the variant as being a major cause of hereditary prostate cancer.

Cases/controls case+ case– control+ control– p-value odds ratio
Prostate cancer
2 361 3 204 0.3589 0.377



Other external references

    Web search results (116 hits -- see all)
  • A Novel Founder Mutation in the RNASEL Gene, 471delAAAG, Is ...
    A Novel Founder Mutation in the RNASEL Gene, 471delAAAG, Is Associated with Prostate Cancer in Ashkenazi Jews ... One of the RNASEL mutations, E265X, was also associated with ...
  • Germline Alterations of the RNASEL Gene, a Candidate HPC1 ...
    The RNASEL gene (2′,5′-oligoisoadenylate-synthetase dependent) ... The E265X variant has been proven to cause a dramatic decrease in the enzymatic activity of RNASEL (Dong and ...
  • Germline Alterations of the RNASEL Gene, a Candidate HPC1 ...
    The RNASEL gene (2 ,5 -oligoisoadenylate-synthetase dependent) encodes a ribonuclease ... Truncating Mutation E265X and Missense Variant R462Q of the RNASEL ...
  • British Journal of Cancer - Mutation screening and ...
    Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene ... could be explained by RNASEL mutations like E265X, although presently ...
  • doi:10.1086/342775
    HPC1/RNASEL was recently identified as a candidate gene for hereditary ... One of the RNASEL mutations, E265X, was also. associated with hereditary prostate cancer ...
  • RNASEL - SNPedia
    The ribonuclease L (RNase L; RNASEL) gene encodes a key enzyme in the interferon induced ... an rs# in dbSNP, known as E265X, associated with an 11 year earlier ...
    Mutations in RNASEL segregate with the disease in prostate. cancer families and specific ... Cells from carriers of M1I and E265X showed half the normal ...
  • PLoS ONE: Germline Mutation in RNASEL Predicts Increased Risk ...
    PLoS ONE: an inclusive, peer-reviewed, open-access resource from the PUBLIC LIBRARY OF ... The mutations of I97L and E265X are positioned in the ankyrin repeat three and seven, ...
  • Genetics of Prostate Cancer - National Cancer Institute
    Expert-reviewed information summary about the genetics of prostate cancer, including ... case-control studies that contained data on the RNASEL variants E265X, R462Q and D541E. ...
  • British Journal of Cancer - Abstract of article: Mutation ...
    RNASEL, encoding the 2',5'-oligoadenylate-dependant RNase L, seems to have rare ... conspicuous RNASEL variants with prostate cancer: the nonsense mutation E265X, and a ...

Other in silico analyses

  • NBLOSUM100 score = 10
  • GET-Evidence autoscore = 5

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Gene search

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