Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2004 Jun;41(6):474–480. doi: 10.1136/jmg.2003.017996

A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO

D Evans 1, D Eccles 1, N Rahman 1, K Young 1, M Bulman 1, E Amir 1, A Shenton 1, A Howell 1, F Lalloo 1
PMCID: PMC1735807  PMID: 15173236

Abstract

Methods: DNA samples from affected subjects from 422 non-Jewish families with a history of breast and/or ovarian cancer were screened for BRCA1 mutations and a subset of 318 was screened for BRCA2 by whole gene screening techniques. Using a combination of results from screening and the family history of mutation negative and positive kindreds, a simple scoring system (Manchester scoring system) was devised to predict pathogenic mutations and particularly to discriminate at the 10% likelihood level. A second separate dataset of 192 samples was subsequently used to test the model's predictive value. This was further validated on a third set of 258 samples and compared against existing models.

Results: The scoring system includes a cut-off at 10 points for each gene. This equates to >10% probability of a pathogenic mutation in BRCA1 and BRCA2 individually. The Manchester scoring system had the best trade-off between sensitivity and specificity at 10% prediction for the presence of mutations as shown by its highest C-statistic and was far superior to BRCAPRO.

Conclusion: The scoring system is useful in identifying mutations particularly in BRCA2. The algorithm may need modifying to include pathological data when calculating whether to screen for BRCA1 mutations. It is considerably less time-consuming for clinicians than using computer models and if implemented routinely in clinical practice will aid in selecting families most suitable for DNA sampling for diagnostic testing.

Full Text

The Full Text of this article is available as a PDF (136.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antoniou A. C., Pharoah P. D. P., McMullan G., Day N. E., Stratton M. R., Peto J., Ponder B. J., Easton D. F. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer. 2002 Jan 7;86(1):76–83. doi: 10.1038/sj.bjc.6600008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Atkinson Charlotte, Bingham Sheila A. Mammographic breast density as a biomarker of effects of isoflavones on the female breast. Breast Cancer Res. 2001 Oct 25;4(1):1–4. doi: 10.1186/bcr410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berry Donald A., Iversen Edwin S., Jr, Gudbjartsson Daniel F., Hiller Elaine H., Garber Judy E., Peshkin Beth N., Lerman Caryn, Watson Patrice, Lynch Henry T., Hilsenbeck Susan G. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol. 2002 Jun 1;20(11):2701–2712. doi: 10.1200/JCO.2002.05.121. [DOI] [PubMed] [Google Scholar]
  4. Couch F. J., DeShano M. L., Blackwood M. A., Calzone K., Stopfer J., Campeau L., Ganguly A., Rebbeck T., Weber B. L. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med. 1997 May 15;336(20):1409–1415. doi: 10.1056/NEJM199705153362002. [DOI] [PubMed] [Google Scholar]
  5. Domchek Susan M., Eisen Andrea, Calzone Kathleen, Stopfer Jill, Blackwood Anne, Weber Barbara L. Application of breast cancer risk prediction models in clinical practice. J Clin Oncol. 2003 Feb 15;21(4):593–601. doi: 10.1200/JCO.2003.07.007. [DOI] [PubMed] [Google Scholar]
  6. Eccles D. M., Englefield P., Soulby M. A., Campbell I. G. BRCA1 mutations in southern England. Br J Cancer. 1998 Jun;77(12):2199–2203. doi: 10.1038/bjc.1998.366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ellis D., Greenman J., Hodgson S., McCall S., Lalloo F., Cameron J., Izatt L., Scott G., Jacobs C., Watts S. Low prevalence of germline BRCA1 mutations in early onset breast cancer without a family history. J Med Genet. 2000 Oct;37(10):792–794. doi: 10.1136/jmg.37.10.792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Euhus David M., Smith Kristin C., Robinson Linda, Stucky Amy, Olopade Olufunmilayo I., Cummings Shelly, Garber Judy E., Chittenden Anu, Mills Gordon B., Rieger Paula. Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst. 2002 Jun 5;94(11):844–851. doi: 10.1093/jnci/94.11.844. [DOI] [PubMed] [Google Scholar]
  9. Evans D. G. R., Bulman M., Young K., Gokhale D., Lalloo F. Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families. J Med Genet. 2003 Sep;40(9):e107–e107. doi: 10.1136/jmg.40.9.e107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ford D., Easton D. F., Stratton M., Narod S., Goldgar D., Devilee P., Bishop D. T., Weber B., Lenoir G., Chang-Claude J. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998 Mar;62(3):676–689. doi: 10.1086/301749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Frank T. S., Manley S. A., Olopade O. I., Cummings S., Garber J. E., Bernhardt B., Antman K., Russo D., Wood M. E., Mullineau L. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998 Jul;16(7):2417–2425. doi: 10.1200/JCO.1998.16.7.2417. [DOI] [PubMed] [Google Scholar]
  12. Frank Thomas S., Deffenbaugh Amie M., Reid Julia E., Hulick Mark, Ward Brian E., Lingenfelter Beth, Gumpper Kathi L., Scholl Thomas, Tavtigian Sean V., Pruss Dmitry R. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002 Mar 15;20(6):1480–1490. doi: 10.1200/JCO.2002.20.6.1480. [DOI] [PubMed] [Google Scholar]
  13. Ganguly A., Rock M. J., Prockop D. J. Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10325–10329. doi: 10.1073/pnas.90.21.10325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gilpin C. A., Carson N., Hunter A. G. A preliminary validation of a family history assessment form to select women at risk for breast or ovarian cancer for referral to a genetics center. Clin Genet. 2000 Oct;58(4):299–308. doi: 10.1034/j.1399-0004.2000.580408.x. [DOI] [PubMed] [Google Scholar]
  15. Johannesdottir G., Gudmundsson J., Bergthorsson J. T., Arason A., Agnarsson B. A., Eiriksdottir G., Johannsson O. T., Borg A., Ingvarsson S., Easton D. F. High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients. Cancer Res. 1996 Aug 15;56(16):3663–3665. [PubMed] [Google Scholar]
  16. Krainer M., Silva-Arrieta S., FitzGerald M. G., Shimada A., Ishioka C., Kanamaru R., MacDonald D. J., Unsal H., Finkelstein D. M., Bowcock A. Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer. N Engl J Med. 1997 May 15;336(20):1416–1421. doi: 10.1056/NEJM199705153362003. [DOI] [PubMed] [Google Scholar]
  17. Lakhani Sunil R., Van De Vijver Marc J., Jacquemier Jocelyne, Anderson Thomas J., Osin Peter P., McGuffog Lesley, Easton Douglas F. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002 May 1;20(9):2310–2318. doi: 10.1200/JCO.2002.09.023. [DOI] [PubMed] [Google Scholar]
  18. Lalloo F., Cochrane S., Bulman B., Varley J., Elles R., Howell A., Evans D. G. An evaluation of common breast cancer gene mutations in a population of Ashkenazi Jews. J Med Genet. 1998 Jan;35(1):10–12. doi: 10.1136/jmg.35.1.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lalloo Fiona, Varley Jennifer, Ellis David, Moran Anthony, O'Dair Lindsay, Pharoah Paul, Evans D. Gareth R., Early Onset Breast Cancer Study Group Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. Lancet. 2003 Mar 29;361(9363):1101–1102. doi: 10.1016/S0140-6736(03)12856-5. [DOI] [PubMed] [Google Scholar]
  20. Langston A. A., Malone K. E., Thompson J. D., Daling J. R., Ostrander E. A. BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med. 1996 Jan 18;334(3):137–142. doi: 10.1056/NEJM199601183340301. [DOI] [PubMed] [Google Scholar]
  21. Levy-Lahad E., Catane R., Eisenberg S., Kaufman B., Hornreich G., Lishinsky E., Shohat M., Weber B. L., Beller U., Lahad A. Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet. 1997 May;60(5):1059–1067. [PMC free article] [PubMed] [Google Scholar]
  22. Loman N., Johannsson O., Kristoffersson U., Olsson H., Borg A. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001 Aug 15;93(16):1215–1223. doi: 10.1093/jnci/93.16.1215. [DOI] [PubMed] [Google Scholar]
  23. Parmigiani G., Berry D., Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998 Jan;62(1):145–158. doi: 10.1086/301670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peto J., Collins N., Barfoot R., Seal S., Warren W., Rahman N., Easton D. F., Evans C., Deacon J., Stratton M. R. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999 Jun 2;91(11):943–949. doi: 10.1093/jnci/91.11.943. [DOI] [PubMed] [Google Scholar]
  25. Shannon Kristen M., Lubratovich Marcie L., Finkelstein Dianne M., Smith Barbara L., Powell Simon N., Seiden Michael V. Model-based predictions of BRCA1/2 mutation status in breast carcinoma patients treated at an academic medical center. Cancer. 2002 Jan 15;94(2):305–313. doi: 10.1002/cncr.10223. [DOI] [PubMed] [Google Scholar]
  26. Shattuck-Eidens D., Oliphant A., McClure M., McBride C., Gupte J., Rubano T., Pruss D., Tavtigian S. V., Teng D. H., Adey N. BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA. 1997 Oct 15;278(15):1242–1250. [PubMed] [Google Scholar]
  27. Szabo C. I., King M. C. Population genetics of BRCA1 and BRCA2. Am J Hum Genet. 1997 May;60(5):1013–1020. [PMC free article] [PubMed] [Google Scholar]
  28. Vahteristo P., Eerola H., Tamminen A., Blomqvist C., Nevanlinna H. A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families. Br J Cancer. 2001 Mar 2;84(5):704–708. doi: 10.1054/bjoc.2000.1626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Werness B. A., Ramus S. J., Whittemore A. S., Garlinghouse-Jones K., Oakley-Girvan I., Dicioccio R. A., Tsukada Y., Ponder B. A., Piver M. S. Histopathology of familial ovarian tumors in women from families with and without germline BRCA1 mutations. Hum Pathol. 2000 Nov;31(11):1420–1424. [PubMed] [Google Scholar]
  30. de la Hoya M., Díez O., Pérez-Segura P., Godino J., Fernández J. M., Sanz J., Alonso C., Baiget M., Díaz-Rubio E., Caldés T. Pre-test prediction models of BRCA1 or BRCA2 mutation in breast/ovarian families attending familial cancer clinics. J Med Genet. 2003 Jul;40(7):503–510. doi: 10.1136/jmg.40.7.503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. de la Hoya Miguel, Sulleiro Sara, Osorio Ana, Díez Orland, Baiget Montserrat, Benítez Javier, Díaz-Rubio Eduardo, Caldés Trinidad. Clustering of cancer-related mutations in a subset of BRCA1 alleles: a study in the Spanish population. Int J Cancer. 2002 Aug 10;100(5):618–619. doi: 10.1002/ijc.10527. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES