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Novel germline mutations in BRCA2 gene among 96 hereditary breast and breast–ovarian cancer families from Kerala, South India

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Aim of the present study was to identify the genetic heterogeneity, prevalence and frequency of germline mutations of BRCA2 gene in Hereditary Breast/Ovarian cancer patients from Kerala, South India.


We analyzed 102 Breast/Ovarian cancer patients from 96 breast and/ovarian cancer families for BRCA2 gene mutations using Conformation-Sensitive Gel Electrophoresis (CSGE) followed by sequencing.


Sequence variations in BRCA2 gene were detected in 27 (26.4%) patients. Sixteen distinct sequence variants were detected of which 11 were (69%) in exon 11. We have identified two novel disease-causing frameshift mutations (c.4642delAA and c.4926insGACC) in two unrelated patients. Apart from this, fourteen distinct sequence variants were detected in 25 breast/ovarian cancer patients of which 8 (57%) were also novel. These include nine missense mutations, one silent mutation, one-nonsense mutation and three intronic variants.


The results of this study suggest that germline mutations of BRCA2 gene account for rather small proportion of Hereditary Breast/Ovarian cancer in Kerala, South India.

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  1. Bignell G, Micklem G, Stratton MR, Ashworth A, Wooster R (1997) The BRC repeats are conserved in mammalian BRCA2 proteins. Hum Mol Genet 6:53–58

  2. Breast Cancer Information Core, National Center for Human Genome Research, National Institutes of Health (1996)

  3. Chen J, Hedman MZ, Arver BW, Sigurdsson S, Eyfjord JE, Lindblom A (1998) BRCA2 germline mutations in Swedish breast cancer families. Eur J Hum Genet 6:134–139

  4. Claes K, Poppe B, Coene I, Paepe AD, Messiaen L (2004) BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer 90:1244–1251

  5. de la Hoya M, Osorio A, Godino J, Sulleiro S, Tosar A, Perez-Segura P, Fernandez C, Rodriguez R, Diaz-Rubio E, Benitez J, Devilee P, Caldes T (2002) Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer 97:466–471

  6. Easton D (1997) Breast cancer genes—what are the real risks?. Nat Genet 16:210–211

  7. Ellisen LW, Haber DA (1998) Hereditary breast cancer. Annu Rev Med 49:425–436

  8. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families The Breast Cancer Linkage Consortium. Am J Hum Genet 62:676–689

  9. Frank TS, Manley SA, Olopade OI, Cummings S, Garber JE, Bernhardt B, Antman K, Russo D, Wood ME, Mullineau L, Isaacs C, Peshkin B, Buys S, Venne V, Rowley PT, Loader S, Offit K, Robson M, Hampel H, Brener D, Winer EP, Clark S, Weber B, Strong LC, Thomas A (1998) Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 16:2417–2425

  10. Friedman LS, Gayther SA, Kurosaki T, Gordon D, Noble B, Casey G, Ponder BA, Anton-Culver H (1997) Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. Am J Hum Genet 60:313–319

  11. Ganguly A, Rock MJ, Prockop DJ (1993) 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 USA 90:10325–10329

  12. Gauthier-Villars M, Gad S, Caux V, Pages S, Blandy C, Stoppa-Lyonnet D (1999) Genetic testing for breast cancer predisposition. Surg Clin North Am 79:1171–87, xxi

  13. Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, Stratton MR, Easton D (1997) Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15:103–105

  14. Hamann U, Liu X, Lange S, Ulmer HU, Benner A, Scott RJ (2002) Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany. J Med Genet 39:E12

  15. Ikeda N, Miyoshi Y, Yoneda K, Shiba E, Sekihara Y, Kinoshita M, Noguchi S (2001) Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Int J Cancer 91:83–88

  16. Khoo US, Chan KY, Cheung AN, Xue WC, Shen DH, Fung KY, Ngan HY, Choy KW, Pang CP, Poon CS, Poon AY, Ozcelik H (2002) Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: a founder mutation of BRCA1 identified in the Chinese population. Hum Mutat 19:307–308

  17. Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A (2001) 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 93:1215–1223

  18. Mazoyer S, Dunning AM, Serova O, Dearden J, Puget N, Healey CS, Gayther SA, Mangion J, Stratton MR, Lynch HT, Goldgar DE, Ponder BA, Lenoir GM (1996) A polymorphic stop codon in BRCA2. Nat Genet 14:253–254

  19. Parkin DM (2004) International variation. Oncogene 23:6329–6340

  20. Peelen T, van Vliet M, Bosch A, Bignell G, Vasen HF, Klijn JG, Meijers-Heijboer H, Stratton M, van Ommen GJ, Cornelisse CJ, Devilee P (2000) Screening for BRCA2 mutations in 81 Dutch breast–ovarian cancer families. Br J Cancer 82:151–156

  21. Peixoto A, Salgueiro N, Santos C, Varzim G, Rocha P, Soares MJ, Pereira D, Rodrigues H, Bento MJ, Fraguas A, Moura G, Regateiro F, Castedo S, Teixeira MR (2006) BRCA1 and BRCA2 germline mutational spectrum and evidence for genetic anticipation in Portuguese breast/ovarian cancer families. Fam Cancer [Epub ahead of print]

  22. Rahman N, Stratton MR (1998) The genetics of breast cancer susceptibility. Annu Rev Genet 32:95–121

  23. Rajkumar T, Soumittra N, Nancy NK, Swaminathan R, Sridevi V, Shanta V (2003) BRCA1, BRCA2 and CHEK2 (1100 del C) germline mutations in hereditary breast and ovarian cancer families in South India. Asian Pac J Cancer Prev 4:203–208

  24. Salazar R, Cruz-Hernandez JJ, Sanchez-Valdivieso E, Rodriguez CA, Gomez-Bernal A, Barco E, Fonseca E, Portugal T, Gonzalez-Sarmiento R (2006) BRCA1–2 mutations in breast cancer: identification of nine new variants of BRCA1–2 genes in a population from central Western Spain. Cancer Lett 233:172–177

  25. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

  26. Saxena S, Szabo CI, Chopin S, Barjhoux L, Sinilnikova O, Lenoir G, Goldgar DE, Bhatanager D (2002) BRCA1 and BRCA2 in Indian breast cancer patients. Hum Mutat 20:473–474

  27. Saxena S, Chakraborty A, Kaushal M, Kotwal S, Bhatanager D, Mohil RS, Chintamani C, Aggarwal AK, Sharma VK, Sharma PC, Lenoir G, Goldgar DE, Szabo CI (2006) Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in Northern India. BMC Med Genet 7:75

  28. Shih HA, Couch FJ, Nathanson KL, Blackwood MA, Rebbeck TR, Armstrong KA, Calzone K, Stopfer J, Seal S, Stratton MR, Weber BL (2002) BRCA1 and BRCA2 mutation frequency in women evaluated in a breast cancer risk evaluation clinic. J Clin Oncol 20:994–999

  29. Syrjakoski K, Vahteristo P, Eerola H, Tamminen A, Kivinummi K, Sarantaus L, Holli K, Blomqvist C, Kallioniemi OP, Kainu T, Nevanlinna H (2000) Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. J Natl Cancer Inst 92:1529–1531

  30. Thompson D, Easton D (2001) Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68:410–419

  31. Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H, Eyfjord JE (1998) Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 352:1337–1339

  32. Valarmathi MT, Sawhney M, Deo SS, Shukla NK, Das SN (2004) Novel germline mutations in the BRCA1 and BRCA2 genes in Indian breast and breast–ovarian cancer families. Hum Mutat 23:205

  33. Wagner TM, Hirtenlehner K, Shen P, Moeslinger R, Muhr D, Fleischmann E, Concin H, Doeller W, Haid A, Lang AH, Mayer P, Petru E, Ropp E, Langbauer G, Kubista E, Scheiner O, Underhill P, Mountain J, Stierer M, Zielinski C, Oefner P (1999) Global sequence diversity of BRCA2: analysis of 71 breast cancer families and 95 control individuals of worldwide populations. Hum Mol Genet 8:413–423

  34. Wong AK, Pero R, Ormonde PA, Tavtigian SV, Bartel PL (1997) RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J Biol Chem 272:31941–31944

  35. Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 265:2088–2090

  36. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792

  37. Yazici H, Bitisik O, Akisik E, Cabioglu N, Saip P, Muslumanoglu M, Glendon G, Bengisu E, Ozbilen S, Dincer M, Turkmen S, Andrulis IL, Dalay N, Ozcelik H (2000) BRCA1 and BRCA2 mutations in Turkish breast/ovarian families and young breast cancer patients. Br J Cancer 83:737–742

  38. Zhi X, Szabo C, Chopin S, Suter N, Wang QS, Ostrander EA, Sinilnikova OM, Lenoir GM, Goldgar D, Shi YR (2002) BRCA1 and BRCA2 sequence variants in Chinese breast cancer families. Hum Mutat 20:474

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We are deeply indebted to the patients who accepted to participate in this study. The first author is a recipient of Senior Research Fellowship from Indian Council of Medical Research (ICMR).

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Correspondence to Ravindran Ankathil.

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Syamala, V., Sreeja, L., Syamala, V.S. et al. Novel germline mutations in BRCA2 gene among 96 hereditary breast and breast–ovarian cancer families from Kerala, South India. J Cancer Res Clin Oncol 133, 867–874 (2007).

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  • BRCA2
  • Breast cancer
  • Ovarian cancer
  • Germline mutations
  • CSGE
  • HBOC Families