Mutation detection in the BRCA1 and BRCA2 genes is of great clinical import but is extremely challenging from a technical standpoint. The large variety of mutation types mandates the use of multiple mutation detection methods if a sensitivity approaching 100% is desired. Methods for assessing pretest probability based on clinical presenta-tion33 can be used to determine which cases merit the highest degree of mutational analysis. Further improvements in mutation detection methods are needed to clarify the true sensitivity of testing versus the proportion of families with mutations in other hereditary breast cancer genes. Clinical interpretation is beleaguered by the high prevalence of genetic variants of uncertain significance. Development of functional assays is highly desirable and may help classify variants into benign or disease-causing categories.


1. Pharoah PD, Day NE, Duffy S, Easton DF, Ponder BA. Family history and the risk of breast cancer: a systematic review and meta-analysis. Int J Cancer. 1997;71:800-809.

2. Hemminki K, Granstrom C, Czene K. Attributable risks for familial breast cancer by proband status and morphology: a nationwide epi-demiologic study from Sweden. Int J Cancer. 2002;100:214-219.

3. Offit K. Clinical Cancer Genetics. Risk Counseling and Management. New York: Wiley-Liss; 1998.

4. de Jong MM, Nolte IM, te Meerman GJ, et al. Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility. J Med Genet. 2002;39:225-242.

5. Meijers-Heijboer H, van den OA, Klijn J, et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarri-ers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31:55-59.

6. Thorstenson YR, Roxas A, Kroiss R, et al. Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res. 2003;63:3325-3333.

7. Kaklamani VG, Hou N, Bian Y, et al. TGFBR1*6A and cancer risk: a meta-analysis of seven case-control studies. J Clin Oncol. 2003;21: 3236-3243.

8. Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet. 2002;31:33-36.

9. Newman B, Austin MA, Lee M, King MC. Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci U S A. 1988;85:3044-3048.

10. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250:1684-1689.

11. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66-71.

12. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789-792.

13. Tavtigian SV, Simard J, Rommens J, et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996;12:333-337.

14. Deng CX, Brodie SG. Roles of BRCA1 and its interacting proteins. Bioessays. 2000;22:728-737.

15. Scully R, Livingston DM. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature. 2000;408:429-432.

16. Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20:1480-1490.

17. Byrne TJ, Reece MT, Adams LA, Hoffman DE, Lane MA, Cohn GM. A rapid immunoassay predicts BRCA1 and BRCA2 mutations in buccal cells. Oncol Rep. 2000;7:1203-1207.

18. Byrne TJ, Reece MT, Adams LA, Lane MA, Cohn GM. An antibody assay predictive of BRCA1 mutations in ovarian tumors and normal tissue. Oncol Rep. 2000;7:949-953.

19. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. 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;20:2310-2318.

20. Hedenfalk I, Duggan D, Chen Y, et al. Gene-expression profiles in hereditary breast cancer. N Engl J Med. 2001;344:539-548.

21. Van 't Veer LJ, Dai H, Van De Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530-536.

22. Frank TS, Manley SA,Olopade OI, et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998;16:2417-2425.

23. Ganguly A, Rock MJ, Prockop DJ. 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;90:10325-10329.

24. van Orsouw NJ, Dhanda RK, Rines RD, et al. Rapid design of denaturing gradient-based two-dimensional electrophoretic gene muta-tional scanning tests. Nucleic Acids Res. 1998;26:2398-2406.

25. Wagner T, Stoppa-Lyonnet D, Fleischmann E, et al. Denaturing highperformance liquid chromatography detects reliably BRCA1 and BRCA2 mutations. Genomics. 1999;62:369-376.

26. Buzin CH, Wen CY, Nguyen VQ, et al. Scanning by DOVAM-S detects all unique sequence changes in blinded analyses: evidence that the scanning conditions are generic. Biotechniques. 2000; 28:746-750, 752-753.

27. Nakagawa H, Hampel H, de la Chapelle A. Identification and characterization of genomic rearrangements of MSH2 and MLH1 in Lynch syndrome (HNPCC) by novel techniques. Hum Mutat. 2003;22:258-263.

28. Hendrickson BC, Pruss D, Lyon E, Scholl T. Application of haplotype pair analysis for the identification of hemizygous loci. J Med Genet. 2003;40:346-347.

29. Hogervorst FB, Cornelis RS, Bout M, et al. Rapid detection of BRCA1 mutations by the protein truncation test. Nat Genet. 1995;10: 208-212.

30. Hardy CA. The protein truncation test. Methods Mol Biol. 2002; 187:87-108.

31. Eng C, Brody LC, Wagner TM, et al. Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1. J Med Genet. 2001;38: 824-833.

32. Gross E, Arnold N, Goette J, Schwarz-Boeger U, Kiechle M. A comparison of BRCA1 mutation analysis by direct sequencing, SSCP and DHPLC. Hum Genet. 1999;105:72-78.

33. Rubinstein WS, O'Neill SM, Peters JA, Rittmeyer LJ, Stadler MP. Mathematical modeling for breast cancer risk assessment: state of the art and role in medicine. Oncology (Huntington). 2002;16: 1082-1094.

34. Antoniou AC, Pharoah PD, McMullan G, Day NE, Ponder BA, Easton D. Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet Epidemiol. 2001;21:1-18.

35. Ford D, Easton DF, Stratton M, et al. 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;62:676-689.

36. Berry DA, Iversen ES Jr, Gudbjartsson DF, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol. 2002;20: 2701-2712.

37. Puget N, Torchard D, Serova-Sinilnikova OM, et al. A 1-kb Alumediated germ-line deletion removing BRCA1 exon 17. Cancer Res. 1997;57:828-831.

38. Puget N, Stoppa-Lyonnet D, Sinilnikova OM, et al. Screening for germ-line rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions. Cancer Res. 1999;59: 455-461.

39. Puget N, Gad S, Perrin-Vidoz L, et al. Distinct BRCA1 rearrangements involving the BRCA1 pseudogene suggest the existence of a recombination hot spot. Am J Hum Genet. 2002;70:858-865.

40. The BRCA1 Exon 13 Duplication Screening Group. The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. Am J Hum Genet 2000;67(1): 207-212.

41. Petrij-Bosch A, Peelen T, van Vliet M, et al. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet. 1997;17:341-345.

42. Unger MA, Nathanson KL, Calzone K, et al. Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet. 2000;67:841-850.

43. Hendrickson B, Deffenbaugh AM, Gaglio CA, et al. Prevalence results for five recurrent BRCA1 rearrangement mutations in 7570 analyses. Am J Hum Genet. 2003;73(5):487.

44. Frolov A, Prowse AH, Vanderveer L, Bove B, Wu H, Godwin AK. DNA array-based method for detection of large rearrangements in the BRCA1 gene. Genes Chromosomes Cancer. 2002;35:232-241.

45. Gad S, Scheuner MT, Pages-Berhouet S, et al. Identification of a large rearrangement of the BRCA1 gene using colour bar code on combed DNA in an American breast/ovarian cancer family previously studied by direct sequencing. J Med Genet. 2001;38:388-392.

46. Szabo CI, King MC. Population genetics of BRCA1 and BRCA2. Am J Hum Genet. 1997;60:1013-1020.

47. Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996;14:185-187.

48. Kauff ND, Perez-Segura P, Robson ME, et al. Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families. J Med Genet. 2002;39:611-614.

49. Thorlacius S, Sigurdsson S, Bjarnadottir H, et al. Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet. 1997;60:1079-1084.

50. Moller P, Heimdal K, Apold J, et al. Genetic epidemiology of BRCA1 mutations in Norway. Eur J Cancer. 2001;37:2428-2434.

51. Einbeigi Z, Bergman A, Kindblom LG, et al. A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer. Eur J Cancer. 2001;37:1904-1909.

52. Menkiszak J, Gronwald J, Gorski B, et al. Hereditary ovarian cancer in Poland. Int J Cancer. 2003;106:942-945.

53. Olopade OI, Fackenthal JD, Dunston G, Tainsky MA, Collins F, Whitfield-Broome C. Breast cancer genetics in African Americans. Cancer. 2003;97(suppl):236-245.

54. Deffenbaugh AM, Frank TS, Hoffman M, Cannon-Albright L, Neuhausen SL. Characterization of common BRCA1 and BRCA2 variants. Genet Test. 2002;6:119-121.

55. Fleming MA, Potter JD, Ramirez CJ, Ostrander GK, Ostrander EA. Understanding missense mutations in the BRCA1 gene: an evolutionary approach. Proc Natl Acad Sci U S A. 2003;100:1151-1156.

56. Petrucelli N, Lazebnik N, Huelsman KM, Lazebnik RS. Clinical interpretation and recommendations for patients with a variant of uncertain significance in BRCA1 or BRCA2: a survey of genetic counseling practice. Genet Test. 2002;6:107-113.

57. Lynch HT, Snyder CL, Lynch JF, Riley BD, Rubinstein WS. Hereditary breast-ovarian cancer at the bedside: role of the medical oncologist. J Clin Oncol. 2003;21:740-753.

58. Narod SA. Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer. 2002;2:113-123.

59. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643-646.

60. Scheuer L, Kauff N, Robson M, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol. 2002;20:1260-1268.

61. Muhr D,Wagner T, Oefner PJ. Polymerase chain reaction fidelity and denaturing high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;782:105-110.

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