Skip to main content

Advertisement

SpringerLink
Log in

Next-Generation Sequencing for Inherited Breast Cancer Risk: Counseling through the Complexity

  • Breast Cancer (B Overmoyer, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Next-generation sequencing technology affords an unprecedented opportunity to analyze multiple breast cancer susceptibility genes simultaneously. With the incarnation of gene panels that combine testing for moderate- and high-penetrance genes, this technology has given birth to a paradigm shift in clinical genetic test offerings. A transformation in genetic counseling for cancer susceptibility will necessarily follow, with a shift from the traditional approach of single-gene testing to considerations of testing by multi-gene panels. At the same time, however, the opportunity to identify rare lesions underlying hereditary susceptibility has introduced new challenges. Available cancer risk estimates for genes included in panel tests may not be supported by evidence, and there is increased risk of identifying variants of uncertain significance (VUS). Management of individuals with rare pathogenic mutations may be unclear. We provide a summary of available evidence for breast cancer risks conferred by pathogenic mutations in genes commonly included in breast cancer susceptibility panels, as well as a review of limitations and counseling points.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf.

  3. 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(9):3044–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Ellis NA, Offit K. Heterozygous mutations in DNA repair genes and hereditary breast cancer: a question of power. PLoS Genet. 2012;8(9):e1003008.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Complexo, Southey MC, Park DJ, Nguyen-Dumont T, Campbell I, Thompson E, et al. COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration. BCR. 2013;15(3):402.

    Google Scholar 

  6. Mardis ER. A decade's perspective on DNA sequencing technology. Nature. 2011;470(7333):198–203.

    Article  CAS  PubMed  Google Scholar 

  7. Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(44):18032–7. Massive parallel sequencing identified germline mutations in 23% of women with ovarian cancer.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Domchek SM, Bradbury A, Garber JE, Offit K, Robson ME. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(10):1267–70.

    Article  Google Scholar 

  9. King MC, Lee GM, Spinner NB, Thomson G, Wrensch MR. Genetic epidemiology. Annu Rev Public Health. 1984;5:1–52.

    Article  CAS  PubMed  Google Scholar 

  10. Plon SE, Eccles DM, Easton D, Foulkes WD, Genuardi M, Greenblatt MS, et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 2008;29(11):1282–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet Med Off J Am Coll Med Genet. 2008;10(4):294–300.

    CAS  Google Scholar 

  12. Hilbers F, Vreeswijk M, van Asperen C, Devilee P. The impact of next generation sequencing on the analysis of breast cancer susceptibility: a role for extremely rare genetic variation? Clin Genet. 2013;84(5):407–14.

    Article  CAS  PubMed  Google Scholar 

  13. Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250(4988):1684–9.

    Article  CAS  PubMed  Google Scholar 

  14. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66–71.

    Article  CAS  PubMed  Google Scholar 

  15. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378(6559):789–92.

    Article  CAS  PubMed  Google Scholar 

  16. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108(2):171–82.

    Article  CAS  PubMed  Google Scholar 

  17. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer. 2000;83(10):1301–8.

  18. Offit K, Gilewski T, McGuire P, Schluger A, Hampel H, Brown K, et al. Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet. 1996;347(9016):1643–5.

    Article  CAS  PubMed  Google Scholar 

  19. Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, et al. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996;14(2):188–90.

    Article  CAS  PubMed  Google Scholar 

  20. Domchek SM, Tang J, Stopfer J, Lilli DR, Hamel N, Tischkowitz M, et al. Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discov. 2013;3(4):399–405.

    Article  CAS  PubMed  Google Scholar 

  21. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297(5581):606–9.

    Article  CAS  PubMed  Google Scholar 

  22. Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22(6):719–29.

    Article  CAS  PubMed  Google Scholar 

  23. Oliver AW, Swift S, Lord CJ, Ashworth A, Pearl LH. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 2009;10(9):990–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Southey MC, Teo ZL, Winship I. PALB2 and breast cancer: ready for clinical translation! Appl Clin Genet. 2013;6:43–52. A comprehensive review article summarizing the current data on germline PALB2 mutations.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39(2):162–4.

    Article  CAS  PubMed  Google Scholar 

  26. Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Erkko H, Dowty JG, Nikkila J, Syrjakoski K, Mannermaa A, Pylkas K, et al. Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(14):4667–71.

    Article  CAS  Google Scholar 

  28. Malkin D, Jolly KW, Barbier N, Look AT, Friend SH, Gebhardt MC, et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med. 1992;326(20):1309–15.

    Article  CAS  PubMed  Google Scholar 

  29. Malkin D, Li FP, Strong LC, Fraumeni Jr JF, Nelson CE, Kim DH, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250(4985):1233–8.

    Article  CAS  PubMed  Google Scholar 

  30. Nichols KE, Malkin D, Garber JE, Fraumeni Jr JF, Li FP. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2001;10(2):83–7.

    CAS  Google Scholar 

  31. Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003;63(20):6643–50.

    CAS  PubMed  Google Scholar 

  32. Lalloo F, Evans DG. Familial breast cancer. Clin Genet. 2012;82(2):105–14.

    Article  CAS  PubMed  Google Scholar 

  33. Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295(12):1379–88.

    Article  CAS  PubMed  Google Scholar 

  34. Birch JM, Hartley AL, Tricker KJ, Prosser J, Condie A, Kelsey AM, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54(5):1298–304.

    CAS  PubMed  Google Scholar 

  35. Masciari S, Dillon DA, Rath M, Robson M, Weitzel JN, Balmana J, et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat. 2012;133(3):1125–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Melhem-Bertrandt A, Bojadzieva J, Ready KJ, Obeid E, Liu DD, Gutierrez-Barrera AM, et al. Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer. 2012;118(4):908–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Wilson JR, Bateman AC, Hanson H, An Q, Evans G, Rahman N, et al. A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet. 2010;47(11):771–4.

    Article  CAS  PubMed  Google Scholar 

  38. Rath MG, Masciari S, Gelman R, Miron A, Miron P, Foley K, et al. Prevalence of germline TP53 mutations in HER2+ breast cancer. Breast Cancer Res Treat. 2013;139(1):193–8.

    Article  CAS  PubMed  Google Scholar 

  39. Garritano S, Gemignani F, Palmero EI, Olivier M, Martel-Planche G, Le Calvez-Kelm F, et al. Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect. Hum Mutat. 2010;31(2):143–50.

    Article  CAS  PubMed  Google Scholar 

  40. Assumpcao JG, Seidinger AL, Mastellaro MJ, Ribeiro RC, Zambetti GP, Ganti R, et al. Association of the germline TP53 R337H mutation with breast cancer in southern Brazil. BMC Cancer. 2008;8:357.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, et al. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet. 1996;13(1):114–6.

    Article  CAS  PubMed  Google Scholar 

  42. Bubien V, Bonnet F, Brouste V, Hoppe S, Barouk-Simonet E, David A, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet. 2013;50(4):255–63.

    Article  CAS  PubMed  Google Scholar 

  43. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res Off J Am Assoc Cancer Res. 2012;18(2):400–7.

    Article  CAS  Google Scholar 

  44. Piccione M, Fragapane T, Antona V, Giachino D, Cupido F, Corsello G. PTEN hamartoma tumor syndromes in childhood: description of two cases and a proposal for follow-up protocol. Am J Med Genet A. 2013;161A(11):2902–8.

    Article  PubMed  Google Scholar 

  45. Pilarski R, Stephens JA, Noss R, Fisher JL, Prior TW. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet. 2011;48(8):505–12.

    Article  CAS  PubMed  Google Scholar 

  46. McGarrity TJ, Amos CI, Frazier ML, Wei C. Peutz-Jeghers Syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews. Seattle (WA); 1993.

  47. van Lier MG, Wagner A, Mathus-Vliegen EM, Kuipers EJ, Steyerberg EW, van Leerdam ME. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010;105(6):1258–64. author reply 65.

    Article  PubMed  Google Scholar 

  48. NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening http://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf49.

  49. Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392(6674):402–5.

    Article  CAS  PubMed  Google Scholar 

  50. Schrader KA, Masciari S, Boyd N, Salamanca C, Senz J, Saunders DN, et al. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet. 2011;48(1):64–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Fitzgerald RC, Hardwick R, Huntsman D, Carneiro F, Guilford P, Blair V, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010;47(7):436–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Offit K, Garber JE. Time to check CHEK2 in families with breast cancer? J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(4):519–20.

    Article  Google Scholar 

  53. Cybulski C, Wokolorczyk D, Jakubowska A, Huzarski T, Byrski T, Gronwald J, et al. Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(28):3747–52.

    Article  CAS  Google Scholar 

  54. Weischer M, Nordestgaard BG, Pharoah P, Bolla MK, Nevanlinna H, Van't Veer LJ, et al. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(35):4308–16.

    Article  CAS  Google Scholar 

  55. Ma X, Zhang B, Zheng W. Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Gut. 2013;63(2):326–36.

    Google Scholar 

  56. Adank MA, Verhoef S, Oldenburg RA, Schmidt MK, Hooning MJ, Martens JW, et al. Excess breast cancer risk in first degree relatives of CHEK2 *1100delC positive familial breast cancer cases. Eur J Cancer. 2013;49(8):1993–9.

    Article  CAS  PubMed  Google Scholar 

  57. Narod SA. Testing for CHEK2 in the cancer genetics clinic: ready for prime time? Clin Genet. 2010;78(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  58. Cybulski C, Huzarski T, Byrski T, Gronwald J, Debniak T, Jakubowska A, et al. Estrogen receptor status in CHEK2-positive breast cancers: implications for chemoprevention. Clin Genet. 2009;75(1):72–8.

    Article  CAS  PubMed  Google Scholar 

  59. Adank MA, Jonker MA, Kluijt I, van Mil SE, Oldenburg RA, Mooi WJ, et al. CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women. J Med Genet. 2011;48(12):860–3.

    Article  CAS  PubMed  Google Scholar 

  60. Huijts PE, Hollestelle A, Balliu B, Houwing-Duistermaat JJ, Meijers CM, Blom JC, et al. CHEK2*1100delC homozygosity in the Netherlands-prevalence and risk of breast and lung cancer. Eur J Hum Genet. 2013;22(1):46–51.

    Google Scholar 

  61. Lavin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008;9(10):759–69.

    Article  CAS  PubMed  Google Scholar 

  62. Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med. 1987;316(21):1289–94.

    Article  CAS  PubMed  Google Scholar 

  63. Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene. 2006;25(43):5906–11.

    Article  CAS  PubMed  Google Scholar 

  64. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38(8):873–5.

    Article  CAS  PubMed  Google Scholar 

  65. Stracker TH, Petrini JH. The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol. 2011;12(2):90–103.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998;93(3):467–76.

    Article  CAS  PubMed  Google Scholar 

  67. Varon R, Reis A, Henze G, von Einsiedel HG, Sperling K, Seeger K. Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res. 2001;61(9):3570–2.

    CAS  PubMed  Google Scholar 

  68. Zhang B, Beeghly-Fadiel A, Long J, Zheng W. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol. 2011;12(5):477–88.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Steffen J, Nowakowska D, Niwinska A, Czapczak D, Kluska A, Piatkowska M, et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int J Cancer J Int du Cancer. 2006;119(2):472–5.

    Article  CAS  Google Scholar 

  70. Narod SA. Genetic variants associated with breast-cancer risk. Lancet Oncol. 2011;12(5):415–6.

    Article  PubMed  Google Scholar 

  71. Heikkinen K, Rapakko K, Karppinen SM, Erkko H, Knuutila S, Lundan T, et al. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis. 2006;27(8):1593–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Roznowski K, Januszkiewicz-Lewandowska D, Mosor M, Pernak M, Litwiniuk M, Nowak J. I171V germline mutation in the NBS1 gene significantly increases risk of breast cancer. Breast Cancer Res Treat. 2008;110(2):343–8.

    Article  CAS  PubMed  Google Scholar 

  73. Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell. 1999;99(6):577–87.

    Article  CAS  PubMed  Google Scholar 

  74. Taylor AM, Groom A, Byrd PJ. Ataxia-telangiectasia-like disorder (ATLD)-its clinical presentation and molecular basis. DNA Repair. 2004;3(8–9):1219–25.

    Article  CAS  PubMed  Google Scholar 

  75. Bartkova J, Tommiska J, Oplustilova L, Aaltonen K, Tamminen A, Heikkinen T, et al. Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol Oncol. 2008;2(4):296–316.

    Article  PubMed  Google Scholar 

  76. Heikkinen K, Karppinen SM, Soini Y, Makinen M, Winqvist R. Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility. J Med Genet. 2003;40(12):e131.

    Article  CAS  PubMed  Google Scholar 

  77. Tommiska J, Seal S, Renwick A, Barfoot R, Baskcomb L, Jayatilake H, et al. Evaluation of RAD50 in familial breast cancer predisposition. Int J Cancer J Int du Cancer. 2006;118(11):2911–6.

    Article  CAS  Google Scholar 

  78. Park YB, Chae J, Kim YC, Cho Y. Crystal structure of human Mre11: understanding tumorigenic mutations. Structure. 2011;19(11):1591–602.

    Article  CAS  PubMed  Google Scholar 

  79. Schiller CB, Lammens K, Guerini I, Coordes B, Feldmann H, Schlauderer F, et al. Structure of Mre11-Nbs1 complex yields insights into ataxia-telangiectasia-like disease mutations and DNA damage signaling. Nat Struct Mol Biol. 2012;19(7):693–700.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Levitus M, Waisfisz Q, Godthelp BC, de Vries Y, Hussain S, Wiegant WW, et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet. 2005;37(9):934–5.

    Article  CAS  PubMed  Google Scholar 

  81. Litman R, Peng M, Jin Z, Zhang F, Zhang J, Powell S, et al. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005;8(3):255–65.

    Article  CAS  PubMed  Google Scholar 

  82. Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001;105(1):149–60.

    Article  CAS  PubMed  Google Scholar 

  83. Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38(11):1239–41.

    Article  CAS  PubMed  Google Scholar 

  84. Rafnar T, Gudbjartsson DF, Sulem P, Jonasdottir A, Sigurdsson A, Jonasdottir A, et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011;43(11):1104–7.

    Article  CAS  PubMed  Google Scholar 

  85. Out AA, Wasielewski M, Huijts PE, van Minderhout IJ, Houwing-Duistermaat JJ, Tops CM, et al. MUTYH gene variants and breast cancer in a Dutch case-control study. Breast Cancer Res Treat. 2012;134(1):219–27.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Rennert G, Lejbkowicz F, Cohen I, Pinchev M, Rennert HS, Barnett-Griness O. MutYH mutation carriers have increased breast cancer risk. Cancer. 2012;118(8):1989–93.

    Article  CAS  PubMed  Google Scholar 

  87. Zhu M, Chen X, Zhang H, Xiao N, Zhu C, He Q, et al. AluYb8 insertion in the MUTYH gene and risk of early-onset breast and gastric cancers in the Chinese population. APJCP. 2011;12(6):1451–5.

    PubMed  Google Scholar 

  88. Win AK, Lindor NM, Jenkins MA. Risk of breast cancer in Lynch syndrome: a systematic review. BCR. 2013;15(2):R27.

    Article  CAS  PubMed  Google Scholar 

  89. Gracia-Aznarez FJ, Fernandez V, Pita G, Peterlongo P, Dominguez O, de la Hoya M, et al. Whole exome sequencing suggests much of non-BRCA1/BRCA2 familial breast cancer is due to moderate and low penetrance susceptibility alleles. PloS One. 2013;8(2):e55681.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Thompson ER, Doyle MA, Ryland GL, Rowley SM, Choong DY, Tothill RW, et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet. 2012;8(9):e1002894.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Irene R. Rainville and Huma Q. Rana declare that they have no conflict of interest

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. 450 Brookline Avenue, Boston, MA, 02115, USA

    Irene R. Rainville & Huma Q. Rana

Authors
  1. Irene R. Rainville
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huma Q. Rana
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huma Q. Rana.

Additional information

This article is part of the Topical Collection on Breast Cancer

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rainville, I.R., Rana, H.Q. Next-Generation Sequencing for Inherited Breast Cancer Risk: Counseling through the Complexity. Curr Oncol Rep 16, 371 (2014). https://doi.org/10.1007/s11912-013-0371-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-013-0371-z

Keywords

Search

Navigation