Breast Cancer Research and Treatment

, Volume 127, Issue 3, pp 853–859 | Cite as

BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer

  • Michelle W. Wong
  • Cecilia Nordfors
  • David Mossman
  • Gordana Pecenpetelovska
  • Kelly A. Avery-Kiejda
  • Bente Talseth-Palmer
  • Nikola A. Bowden
  • Rodney J. Scott
Brief Report


Mutations in the recognized breast cancer susceptibility genes BRCA1, BRCA2, TP53, ATM, and CHEK2 account for approximately 20% of hereditary breast cancer. This raises the possibility that mutations in other biologically relevant genes may be involved in genetic predisposition to breast cancer. In this study, BRIP1, PALB2, and RAD51C were sequenced for mutations as a result of previously being associated with breast cancer risk due to their role in the double-strand break repair pathway and their close association with BRCA1 and BRCA2. Two truncating mutations in PALB2 (Q66X and W1038X), one of which is has not been reported before, were detected in an independent Australian cohort of 70 individuals with breast or ovarian cancer, and have strong family histories of breast or breast/ovarian cancer. In addition, six missense variants predicted to be causative were detected, one in BRIP1 and five in PALB2. No causative variants were identified in RAD51C. This study supports recent observations that although rare, PALB2 mutations are present in a small but substantial proportion of inherited breast cancer cases, and indicates that RAD51C at a population level does not account for a substantial number of familial breast cancer cases.


Hereditary breast cancer BRIP1 PALB2 RAD51C Germline mutations 



Acute myeloid leukemia


Fanconi anemia


Multiplex ligation-dependent probe amplification


Polymerase chain reaction


Single nucleotide polymorphism



We would like to thank all the patients for their consent to the use of their samples in this study. We would also like to acknowledge Dr. Allan Spigelman, Claire Groombridge, and Margaret Gleeson for providing patient samples and family information. This study was supported by Grant from National Breast Cancer Foundation (NBCF), Australia.

Conflict of interest

The authors of this article declare no competing interests related to the study and no commercial associations that may pose a conflict of interest.


  1. 1.
    Lynch HT, Krush AJ (1971) Carcinoma of the breast and ovary in three families. Surg Gynecol Obstet 133(4):644–648PubMedGoogle Scholar
  2. 2.
    Lynch HT, Krush AJ, Lemon HM, Kaplan AR, Condit PT, Bottomley RH (1972) Tumor variation in families with breast cancer. JAMA 222(13):1631–1635PubMedCrossRefGoogle Scholar
  3. 3.
    Lynch HT, Guirgis HA, Albert S, Brennan M, Lynch J, Kraft C et al (1974) Familial association of carcinoma of the breast and ovary. Surg Gynecol Obstet 138(5):717–724PubMedGoogle Scholar
  4. 4.
    National breast and ovarian cancer centre. Breast Cancer. (2009);
  5. 5.
    National Breast and Ovarian Cancer Centre (2009) Breast cancer risk factors: a review of the evidence. National Breast and Ovarian Cancer Centre, Surry Hills, NSWGoogle Scholar
  6. 6.
    Wooster R, Weber BL (2003) Breast and ovarian cancer. NEJM 348(23):2339–2347PubMedCrossRefGoogle Scholar
  7. 7.
    Nathanson KL, Wooster R, Weber BL (2001) Breast cancer genetics: what we know and what we need. Nat Med 7(5):552–556PubMedCrossRefGoogle Scholar
  8. 8.
    Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40(1):17–22PubMedCrossRefGoogle Scholar
  9. 9.
    Turnbull C, Rahman N (2008) Genetic predisposition to breast cancer: past, present and future. Annu Rev Genom Hum Genet 9:321–345CrossRefGoogle Scholar
  10. 10.
    Easton DF, Bishop DT, Ford D, Crockford GP, Consortium BCL (1993) Genetic linkage analysis in familial breast and ovarian cancer. Am J Hum Genet 52(4):678–701PubMedGoogle Scholar
  11. 11.
    Couch FJ, DeShano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L et al (1997) BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. NEJM 336(20):1409–1415PubMedCrossRefGoogle Scholar
  12. 12.
    Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676–689PubMedCrossRefGoogle Scholar
  13. 13.
    Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N et al (1999) Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. JNCI 91(11):943–949PubMedGoogle Scholar
  14. 14.
    Stoppa-Lyonnet D, Laurent-Puig P, Essioux L, Pages S, Ithier G, Ligot L, Institut Curie Breast Cancer Group et al (1997) BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Am J Hum Genet 60(5):1021–1030PubMedGoogle Scholar
  15. 15.
    Rosa-Rosa JM, Pita G, Urioste M, Llort G, Brunet J, Lázaro C et al (2009) Genome-wide linkage scan reveals three putative breast-cancer susceptibility loci. Am J Hum Genet 84(2):115–122PubMedCrossRefGoogle Scholar
  16. 16.
    Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M et al. (2010) Genome-wide assocation study identifies five new breast cancer susceptibility loci. Nat Genet. doi: 10.1038/ng.586
  17. 17.
    Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093PubMedCrossRefGoogle Scholar
  18. 18.
    Smith P, McGuffog L, Easton DF, Mann GJ, Pupo GM, Newman B et al (2006) A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45(7):646–655PubMedCrossRefGoogle Scholar
  19. 19.
    Gold B, Kirchhoff T, Stefanov S, Lautenberger J, Viale A, Garber J et al (2008) Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci USA 105(11):4340–4345PubMedCrossRefGoogle Scholar
  20. 20.
    Cox DG, Penney K, Guo Q, Hankinson SE, Hunter DJ (2007) TGFB1 and TGFBR1 polymorphisms and breast cancer risk in the Nurses’ Health Study. BMC Cancer 7(175):175PubMedCrossRefGoogle Scholar
  21. 21.
    Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D et al (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42(5):410–414PubMedCrossRefGoogle Scholar
  22. 22.
    Levy-Lahad E (2010) Fanconi anemia and breast cancer susceptibility meet again. Nat Genet 42(5):368–369PubMedCrossRefGoogle Scholar
  23. 23.
    Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R et al (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38(11):1239–1241PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang F, Fan Q, Ren K, Auerbach AD, Andreassen PR (2010) FANCJ/BRIP1 recruitment and regulation of FANCD2 in DNA damage responses. Chromosoma 119(6):637–649PubMedCrossRefGoogle Scholar
  25. 25.
    Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N et al (2006) Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 22(6):719–729PubMedCrossRefGoogle Scholar
  26. 26.
    Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A et al (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39(2):165–167PubMedCrossRefGoogle Scholar
  27. 27.
    Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q et al (2007) Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 39(2):159–161PubMedCrossRefGoogle Scholar
  28. 28.
    Levran O, Attwooll C, Henry RT, Milton KL, Neveling K, Rio P et al (2005) The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 37(9):931–933PubMedCrossRefGoogle Scholar
  29. 29.
    Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V et al (2010) Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42(5):406–409PubMedCrossRefGoogle Scholar
  30. 30.
    Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S et al (2001) BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105(1):149–160PubMedCrossRefGoogle Scholar
  31. 31.
    Yu X, Chini CC, He M, Mer G, Chen J (2003) The BRCT domain is a phospho-protein binding domain. Science 302(5645):639–642PubMedCrossRefGoogle Scholar
  32. 32.
    Cantor S, Drapkin R, Zhang F, Lin Y, Han J, Pamidi S et al (2004) The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad Sci USA 101(8):2357–2362PubMedCrossRefGoogle Scholar
  33. 33.
    Sy SM, Huen MS, Chen J (2009) PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci USA 106(17):7155–7160PubMedCrossRefGoogle Scholar
  34. 34.
    Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R et al (2007) Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39(2):162–164PubMedCrossRefGoogle Scholar
  35. 35.
    Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J et al (1997) Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88(2):265–275PubMedCrossRefGoogle Scholar
  36. 36.
    Venkitaraman AR (2009) Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu Rev Pathol 4:461–487PubMedCrossRefGoogle Scholar
  37. 37.
    Ripperger T, Gadzicki D, Meindl A, Schlegelberger B (2009) Breast cancer susceptibility: current knowledge and implications for genetic counselling. Eur J Hum Genet 17(6):722–731PubMedCrossRefGoogle Scholar
  38. 38.
    Tischkowitz M, Xia B, Sabbaghian N, Reis-Filho JS, Hamel N, Li G et al (2007) Analysis of PALB2/FANCN-associated breast cancer families. PNAS 104(16):6788–6793PubMedCrossRefGoogle Scholar
  39. 39.
    Rutter JL, Smith AM, Dávila MR, Sigurdson AJ, Ruthann MG, Pineda MA et al (2003) Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals. Hum Mutat 22(2):121–128PubMedCrossRefGoogle Scholar
  40. 40.
    Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4(7):1073–1081PubMedCrossRefGoogle Scholar
  41. 41.
    Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31(13):3812–3814PubMedCrossRefGoogle Scholar
  42. 42.
    Bamford S, Dawson E, Forbes S, Clements J, Pettett R, Dogan A et al (2004) The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer 91(2):355–358PubMedGoogle Scholar
  43. 43.
    Da Silva L, Lakhani SR (2010) Pathology of hereditary breast cancer. Mod Pathol 23(Suppl 2):S46–S51PubMedCrossRefGoogle Scholar
  44. 44.
    Palacios J, Honrado E, Osorio A, Cazorla A, Sarrio D, Barroso A et al (2003) Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin Cancer Res 9(10 Pt 1):3606–3614PubMedGoogle Scholar
  45. 45.
    Tischkowitz M, Xia B (2010) PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res 70(19):7353–7359PubMedCrossRefGoogle Scholar
  46. 46.
    Foulkes WD, Ghadirian P, Akbari MR, Hamel N, Giroux S, Sabbaghian N et al (2007) Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French–Canadian women. Breast Cancer Res 9(6):83CrossRefGoogle Scholar
  47. 47.
    Oliver AW, Swift S, Lord CJ, Ashworth A, Pearl LH (2009) Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep 10(9):990–996PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang F, Fan Q, Ren K, Andreassen PR (2009) PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol Cancer Res 7(7):1110–1118PubMedCrossRefGoogle Scholar
  49. 49.
    Zhang F, Ma J, Wu J, Ye L, Cai H, Xia B et al (2009) PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol 19(6):524–529PubMedCrossRefGoogle Scholar
  50. 50.
    Buisson R, Dion-Cote AM, Coulombe Y, Launay H, Cai H, Stasiak AZ et al (2010) Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol 17(10):1247–1254PubMedCrossRefGoogle Scholar
  51. 51.
    Thompson D, Easton DF (2002) Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94(18):1358–1365PubMedGoogle Scholar
  52. 52.
    The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. JNCI 91(15):1310–1316Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Michelle W. Wong
    • 1
  • Cecilia Nordfors
    • 2
  • David Mossman
    • 1
  • Gordana Pecenpetelovska
    • 3
  • Kelly A. Avery-Kiejda
    • 1
  • Bente Talseth-Palmer
    • 1
  • Nikola A. Bowden
    • 1
  • Rodney J. Scott
    • 1
    • 3
  1. 1.Discipline of Medical Genetics and Centre for Information-Based Medicine (CIBM)The University of Newcastle, Hunter Medical Research Institute (HMRI), John Hunter HospitalNewcastleAustralia
  2. 2.Department of Molecular Medicine and Surgery, Karolinska InstitutetKarolinska University Hospital, Solna (L1:00)StockholmSweden
  3. 3.Division of Genetics, Hunter Area Pathology Service (HAPS)John Hunter HospitalNewcastleAustralia

Personalised recommendations