ELAC2 A541T - GET-Evidence



(ELAC2 Ala541Thr)

Short summary

This variant is implicated as causing increased susceptibility to prostate cancer. However the variant has always been seen paired with S217L, it is unclear which variant is causal. Evidence is weak for both; one meta-analysis (Severi et al.) concluded that neither variant was pathogenic, a more recent meta-analysis (Xu et al.) found the data to be significant but the odds ratio was not strong and concluded they are “low-penetrance susceptibility markers of prostate cancer”.

Variant evidence

adjacent to a highly conserved histidine motif, but polyphen prediction is “benign”

See Rebbeck TR et al. 2000 (10986046).

Functional -
Case/Control 2

Xu et al. meta-analysis finds a significant effect around p=0.05

See Xu B et al. 2010 (20231859).

Familial -
Clinical importance
Severity 2

There is a low risk of mortality caused by prostate cancer, even if untreated


Prostate screening is standard regardless of whether an individual has this variant

Penetrance 2

Assuming 14% lifetime risk, 2.3% attributable increased risk (total of 16.3%)

See Xu B et al. 2010 (20231859), unpublished research (below).



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

Case/control numbers are used from cases referenced by Xu et al. (where they note that they only use numbers from the most recent publication when multiple publications used the same data source).

Assuming an allele frequency in controls of 6%, an odds ratio 1.22 implies a frequency of 7.2% frequency in cases. Assuming a lifetime risk of prostate cancer of 14%, this would be associated with an additional 2.3% (total of 16.3%).

Total cases/controls case+ case– control+ control– p-value odds ratio
Prostate cancer
55 855 40 1068 0.0112 1.718


Allele frequency

  • T @ chr17:12899902: 2.8% (297/10758) in EVS
  • T @ chr17:12840626: 2.4% (3/124) in GET-Evidence
  • Frequency shown in summary reports: 2.8% (297/10758)


Rebbeck TR, Walker AH, Zeigler-Johnson C, Weisburg S, Martin AM, Nathanson KL, Wein AJ, Malkowicz SB. Association of HPC2/ELAC2 genotypes and prostate cancer. Am J Hum Genet. 2000 Oct;67(4):1014-9. Epub 2000 Sep 12. PubMed PMID: 10986046; PubMed Central PMCID: PMC1287872.

A screen of 359 prostate cancer cases and 257 controls found this variant, previously implicated in susceptibility to prostate cancer, heterozygously or homozygously in 27 of the cases and 9 of the controls. This has a significance of .037 (2-tailed Fisher’s Exact).

Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P, Desrochers M, Dumont M, Farnham JM, Frank D, Frye C, Ghaffari S, Gupte JS, Hu R, Iliev D, Janecki T, Kort EN, Laity KE, Leavitt A, Leblanc G, McArthur-Morrison J, Pederson A, Penn B, Peterson KT, Reid JE, Richards S, Schroeder M, Smith R, Snyder SC, Swedlund B, Swensen J, Thomas A, Tranchant M, Woodland AM, Labrie F, Skolnick MH, Neuhausen S, Rommens J, Cannon-Albright LA. A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet. 2001 Feb;27(2):172-80. PubMed PMID: 11175785.

In a survey of 429 cases and 148 controls, 42 cases and 5 controls were found to be heterozygous or homozygous for this variant. This has a p-value of 0.014 (two-tailed Fisher’s Exact).

Suarez BK, Gerhard DS, Lin J, Haberer B, Nguyen L, Kesterson NK, Catalona WJ. Polymorphisms in the prostate cancer susceptibility gene HPC2/ELAC2 in multiplex families and healthy controls. Cancer Res. 2001 Jul 1;61(13):4982-4. PubMed PMID: 11431329.

In a survey of 257 unrelated prostate cancer cases and 355 healthy unrelated controls, 25 cases and 13 controls were heterozygous or homozygous for this variant.

Cases/controls case+ case– control+ control– p-value odds ratio
Prostate cancer
25 232 13 342 0.0034 2.835


Meitz JC, Edwards SM, Easton DF, Murkin A, Ardern-Jones A, Jackson RA, Williams S, Dearnaley DP, Stratton MR, Houlston RS, Eeles RA; Cancer Research UK/BPG UK Familial Prostate Cancer Study Collaborators. HPC2/ELAC2 polymorphisms and prostate cancer risk: analysis by age of onset of disease. Br J Cancer. 2002 Oct 7;87(8):905-8. PubMed PMID: 12373607; PubMed Central PMCID: PMC2376179.

Another study tries to split people up by age of onset … they find no significant association between A541T and prostate cancer. Control+ (with A/T or T/T genotype): 22, control-: 435. <=55 years of age case+: 18, case-: 226. >55 years case+: 10, case-: 156. Neither the age-related or combined numbers of cases are significantly enriched for the variant.

Cases/controls case+ case– control+ control– p-value odds ratio
Prostate cancer
28 382 22 435 0.2432 1.449


Camp NJ, Tavtigian SV. Meta-analysis of associations of the Ser217Leu and Ala541Thr variants in ELAC2 (HPC2) and prostate cancer. Am J Hum Genet. 2002 Dec;71(6):1475-8. PubMed PMID: 12515253; PubMed Central PMCID: PMC378598.

This meta-analysis says it’s real. The last author is first author in a previous study that supported this variant as pathogenic.

Severi G, Giles GG, Southey MC, Tesoriero A, Tilley W, Neufing P, Morris H, English DR, McCredie MR, Boyle P, Hopper JL. ELAC2/HPC2 polymorphisms, prostate-specific antigen levels, and prostate cancer. J Natl Cancer Inst. 2003 Jun 4;95(11):818-24. PubMed PMID: 12783937.

This meta-analysis combines some of their own data with other studies and concludes that the variant is not pathogenic.

Robbins CM, Hernandez W, Ahaghotu C, Bennett J, Hoke G, Mason T, Pettaway CA, Vijayakumar S, Weinrich S, Furbert-Harris P, Dunston G, Powell IJ, Carpten JD, Kittles RA. Association of HPC2/ELAC2 and RNASEL non-synonymous variants with prostate cancer risk in African American familial and sporadic cases. Prostate. 2008 Dec 1;68(16):1790-7. PubMed PMID: 18767027.

A study in African American families did not find a correlation between A541T and prostate cancer in sporadic cases (possibly because the variant was quite rare). Sporadic cases: T/T: 0, A/T: 2, A/A: 153. Familial cases: T/T: 0, A/T: 0, A/A: 88. Controls: T/T: 0, A/T: 5, A/A: 291. The combined numbers are used.

Cases/controls case+ case– control+ control– p-value odds ratio
Prostate cancer
2 241 5 291 0.4660 0.483


Xu B, Tong N, Li JM, Zhang ZD, Wu HF. ELAC2 polymorphisms and prostate cancer risk: a meta-analysis based on 18 case-control studies. Prostate Cancer Prostatic Dis. 2010 Mar 16. [Epub ahead of print] PubMed PMID: 20231859.

The most recent meta-analysis of ELAC2 polymorphisms Ser217Leu and Ala541Thr, this concludes that these are associated with prostate cancer and may be “low-penetrance susceptibility markers of prostate cancer”. They note that there is publication bias for results supporting pathogenicity (p = 0.011) but that no single paper is necessary for their conclusion of pathogenicity (ie removal of any single paper doesn’t change this result).

Their combined analysis has an odds ratio of 1.22 with a 95% confidence interval 1.00 to 1.48. (An odds ratio of 1.00 would be expected if a variant has no pathogenic effect, so this is barely meeting a significance cutoff.)


hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het T @ chr17:12899902


huE80E3D - CGI sample GS00253-DNA_D01_200_37
het T @ chr17:12899902


GS07357 - var-GS07357-1100-36-ASM
het T @ chr17:12840627


GS19704 - var-GS19704-1100-36-ASM
het T @ chr17:12840627


Other external references

  • rs34152967
  • rs5030739
  • Score: 0.007 (benign)
    Web search results (33 hits -- see all)
  • Mendelian Inheritance in Man Document Reader
    0001 PROSTATE CANCER, SUSCEPTIBILITY TO ELAC2, SER217LEU Rebbeck et al. (2000) demonstrated an increased risk ... The ala541-to-thr (A541T) missense variant lies adjacent to a ...
  • ELAC2 (elaC homolog 2 (E. coli))
    ELAC2 (elaC homolog 2 (E. coli)), Authors: Yang Chen, Sean Tavtigian, Donna Shattuck. Published in: Atlas Genet Cytogenet Oncol Haematol.
  • BioMed Central | Full text | Characterization of TRZ1, a ...
    ELAC2 does not functionally substitute for TRZ1; motifs required for Trz1p function ... of the human ELAC2 missense substitution A541T, which appears to ...
  • Characterization of TRZ1 , a yeast homolog of the human ...
    Like ELAC2 and its other eukaryotic orthologs, TRZ1 can be divided roughly into amino ... corresponds to the missense substitution A541T in ELAC2 that is associated with human ...
  • Genetische Disposition
    Die Bestimmung heute bekannter genetischer Einflüsse kann in vielerlei Hinsicht ... körperliche Aktivität, Umweltgifte), bei der Wahl wirksamer Medikamente und ...
  • Polymorphisms in the Prostate Cancer Susceptibility Gene HPC2 ...
    ... HPC2/ELAC2 that throws translation out of frame after amino acid 547 and that ... The A541T variation was detected by amplification of 37 ng of genomic DNA in 15 ...
  • Selected article
    Science, global weekly of science ... A541T. E622V. Eur Amer. Afr Amer. 888 sporadic. 473 controls. 131 sporadic. 163 controls. no association. no association. no association. 96 ...
  • [Frontiers in Bioscience 11, 1388-1413, May 1, 2006]
    Science, global weekly of science ... ELAC2. A541T, S217L. Rebbeck et al, 2000 (91), N=359 cases, U.S. subjects. Positive association. Suarez et al, 2001 (93), N=257 HPC ...
  • Table 1
    ELAC2. S217L. Prostate cancer. 0.30 and 0.04. Increased risk. Odds ratio ... and A541T (Caucasian) BRCA2. N372H. Breast cancer. 0.22-0.29. Increased risk. Relative risk ...

Other in silico analyses

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 3

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Gene search

"GENE" or "GENE A123C":

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