Gene Mutations in Hereditary Breast Cancer- A Review


  •   Pathima Fairoosa

  •   Chamindri Witharana


The most prevalent form of cancer in females is breast cancer. Roughly 5%-10% of breast cancers are hereditary, and they are associated with Germline gene mutations, inherited from parents. Germline gene mutations increase the risk of developing cancer earlier in life compared to noninherited cases (sporadic cancer). BRCA1 and BRCA2 are well-studied tumour suppressor genes associated with hereditary breast cancer. Even though mutations in BRCA1 and BRCA2 are assumed to responsible the majority of hereditary breast cancers cases, many other breast cancer susceptibility genes have been identified in the last few decades. Identification of many germline mutations was possible due to advance sequencing technologies. Most of these genes are belongs to tumour suppressors and DNA damage repair gene families (DNA double-strand break repair and DNA mismatch repair). These genes play a vital role in genomic stability and cell cycle control suggesting that any alteration in these genes trigger uncontrolled growth and tumour formation. These genes are categorized according to the penetrance level, the proportion of carriers express the associated trait of the mutated gene. Mutations in high penetrance genes such as BRCA1, BRCA2, TP53, PTEN, and SKT11 greatly increase the risk of developing breast cancer. Moderate penetrance gene such as PALB2, ATM, CHEK2, BARD1, BRIP1 and low penetrance gene such as PARP4, CASP8, TOX3 confer moderate to low increase risk of developing breast cancer. Aim of this review is to summarize genes associated with hereditary breast cancer according to their penetrance level (high, moderate and low penetrance).

Keywords: Breast cancer, heredity, susceptibility genes, gene mutations.


V. Trevino. (Augest 2019). Integrative genomic analysis identifies associations of molecular alterations to APOBEC and BRCA1/2 mutational signatures in breast cancer. Mol Genet Genomic Med. 7(8): e810. Available:

B. Vogelstein, N. Papadopoulos, V. Velculescu, S. Zhou, L. A. Diaz and K. W. Kinzler. (March 2013). Cancer Genome Landscapes. Science. 339(6127). pp. 1546-1558. Available:

T. Helleday, S. Eshtad and S. Nik‐Zainal. (July 2014). Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet. 15(9). pp. 585–598. Available: https ://

N.D.W Dissanayake, "Clinical Characterization of a cohort of Sri Lankan families with inherited cancer syndrome", MSc, dissertation, University of Colombo, 2014.

K. Kiwerska and K. Szyfter. (2019). DNA repair in cancer initiation, progression, and therapy - A double-edged sword. J Appl Genet. 60 (3-4) pp. 329-334. Available:

G. Lippi, C. Mattiuzzi and M. Montagnana. (July 2017). BRCA population screening for predicting breast cancer: for or against? Ann Transl Med. 5(13). pp. 275-275, Available:

Y. Wu, F. Liu, S. Luo, X. Yin, D. He, J. Liu, Z. Yue and J. Song. (July 2019).Co-expression of key gene modules and pathways of human breast cancer cell lines. Biosci Rep. 39 (7). Available:

S. Malvia, S. A. R. Bagadi, D. Pradhan, C. Chintamani, A. Bhatnagar, D. Arora, R. Sarin and S. Saxena. (July 2019). Study of Gene Expression Profiles of Breast Cancers in Indian Women. Sci Rep 9(10018). Available:

A. Fernando, U. Jayarajah, S. Prabashani, E. Fernando and S. Seneviratne. (April 2018). Incidence trends and patterns of breast cancer in Sri Lanka: an analysis of the national cancer database. BMC Cancer. 18(482). Available:

P. Apostolou and F. Fostira. (March 2013). Hereditary Breast Cancer: The Era of New Susceptibility Genes. BioMed Res Int. Available:

N. Okumura, H. Yoshida, Y. Kitagishi, Y. Nishimura and S. Matsuda. (September 2011). Alternative splicings on p53, BRCA1 and PTEN genes involved in breast cancer. Biochem Biophys Res Commun. 413(3). pp.395-399. Available:

S. Shiovitz and L. A. Korde. (July 2015). Genetics of breast cancer: a topic in evolution. Ann Oncol. 26(7). pp. 1291-1299. Available:

Z. Baretta, S. Mocellin, E. Goldin, O. Olopade and D. Huo. (October 2016). Effect of BRCA germline mutations on breast cancer prognosis. Medicine. 95(40). e4975. doi: 10.1097/md.0000000000004975

J. D. Fackenthal and O. I. Olopade. (December 2007). Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer. 7(12) pp. 937-948. Available:

K. N. Maxwell and K. L. Nathanson. (December 2013). Common breast cancer risk variants in the post-COGS era: a comprehensive review. Breast Cancer Res. 15(6):212. Available:

U. O. Njiaju and O. I. Olopade. (September 2012). Genetic Determinants of Breast Cancer Risk: A Review of Current Literature and Issues Pertaining to Clinical Application. Breast J. 18(5). pp. 436-442. Available:

A. W. Kurian, K. E. Kingham and J. M. Ford. (February 2015). Next-generation sequencing for hereditary breast and gynecologic cancer risk assessment. Curr Opin Obstet Gynecol. 27(1). pp. 23-33. Available:

P. D. P Pharoah, A. Antoniou, M. Bobrow, R. L. Zimmern, D. F. Easton and B. A. J. Ponder. (May 2002). Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet. 31(1). pp. 33-36, 2002. Available:

W. D. Foulkes. (November 2008). Inherited Susceptibility to Common Cancers. N Engl J Med. 359(20). pp. 2143-2153. Available:

K. N. Maxwell and S. M. Domchek. (September 2012). Cancer treatment according to BRCA1 and BRCA2 mutations. Nat Rev Clin Oncol. 9(9). pp. 520-528. Available:

A. Paul and S. Paul. (January 2014). The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers", Front Biosci (Landmark Ed). 19(4). pp. 605-618. 20. Available:

M. J. Larsen, M. Thomassen, A. N. Gerdes and T. A. Kruse. (October 2014). Hereditary Breast Cancer: Clinical, Pathological and Molecular Characteristics. Breast Cancer (Auckl). 8. pp.145-155. Available:

W. Zhang and Y. Yu. (September 2011). The Important Molecular Markers on Chromosome 17 and Their Clinical Impact in Breast Cancer. Int J Mol Sci, 12(9). pp. 5672-5683. Available:

F. Wang, Q. Fang, Z. Ge, N. Yu, S. Xu and X. Fan. (March 2012). Common BRCA1 and BRCA2 mutations in breast cancer families: a meta-analysis from systematic review. Mol Biol Rep. 39(3). pp. 2109-2118. Available:

O. M. Valencia, S. E. Samuel, R. K. Viscusi, T. Riall, L. A. Neumayer and H. Aziz. (June 2017). The Role of Genetic Testing in Patients with Breast Cancer: A Review. JAMA Surg. vol. 152(6). pp. 589-594. Available:

L. A. R. Oluwagbemiga, A. Oluwole and A. A. R. Kayode. (December 2012). Seventeen years after BRCA1: what is the BRCA mutation status of the breast cancer patients in Africa? – a systematic review", SpringerPlus. 1(1):83. Available:

M. Ratajska, E. Antoszewska, A. Piskorz, I. Brozek, A. Borg, H. Kusmierek, W. Biernat, and J. Limon. (2012). et al., "Cancer predisposing BARD1 mutations in breast-ovarian cancer families", Breast Cancer Res Treat. 131(1). pp.89-97.

P. Economopoulou, G. Dimitriadis and A. Psyrri. (January 2015). Beyond BRCA: New hereditary breast cancer susceptibility genes. Cancer Treat Rev. 41(1), 1–8.

R. Roy, J. Chun and S. Powell. (December 2011). BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 12(1). pp. 68-78. Available:

N. M. Davis, M. Sokolosky, K. Stadelman, S. L. Abrams, M. Libra, S. Candido et al.(July 2014). Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention. Oncotarget. 5(13). pp.4603-4650. Available:

W. Zhang, A. Edwards, E. K. Flemington and K. Zhang (February 2017). Significant Prognostic Features and Patterns of Somatic TP53 Mutations in Human Cancers. Cancer Inform.16. Available:

J. Huszno and E. Grzybowska. (July 2018). TP53 mutations and SNPs as prognostic and predictive factors in patients with breast cancer. Oncol Lett. 16(1). pp.34-40. Available:

A. Patocs, L. Zhang, Y. Xu, F. Weber, T. Caldes, G. L. Mutter, P. Platzer and C. Eng. Breast-Cancer Stromal Cells withTP53Mutations and Nodal Metastases. N Engl J Med. 357(25). pp.2543–2551.

M. Tischkowitz, B. Xia, N. Sabbaghian, J. S. Reis-Filho, N. Hamel, G. Li G, E. H. van Beers, L. Li, T. Khalil, L. A. Quenneville, A. Omeroglu, A. Poll, P. Lepage, N. Wong, P. M. Nederlof, A. Ashworth, P. N. Tonin, S. A. Narod, D. M. Livingston and W. D. Foulkes (April 2007). Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci U S A.104 (16). pp.6788-93. Available:

N. Jones, F. Bonnet, S. Sfar, M. Lafitte, D. Lafon, G. Sierankowski, V. Brouste, G. Banneau, C. Tunon de Lara, M. Debled, G. MacGrogan, M. Longy and N. Sevenet. (July 2013). Comprehensive analysis of PTEN status in breast carcinomas. Int J Cancer. 133(2). pp.323-3. Available:

H. Kobayashi, S. Ohno, Y. Sasaki and M. Matsuura. (June 2013). Hereditary breast and ovarian cancer susceptibility genes (Review). Oncol Rep, 30(3). 1019–1029.

A. D. Skol, M. M. Sasaki and K. Onel. October 2016). The genetics of breast cancer risk in the post-genome era: thoughts on study design to move past BRCA and towards clinical relevance. Breast Cancer Res. 18(1):99. Available:

E. Akisik, H. Yazici and N. Dalay. (January 2011). ARLTS1, MDM2 and RAD51 gene variations are associated with familial breast cancer. Mol Bio Rep. 38(1) pp. 343-348, 2010. Available:

A. R. Venkitaraman. (January 2002). Cancer Susceptibility and the Functions of BRCA1 and BRCA2. Cell. 108(2) pp.171-182. DOI: 10.1016/s0092-8674(02)00615-3

P. Peltomäki. Role of DNA Mismatch Repair Defects in the Pathogenesis of Human Cancer. J Clin Oncol. 21(6). pp. 1174-1179, March 2003.

N. Tung, C. Battelli, B. Allen, R. Kaldate, S. Bhatnagar, K. Bowles, K. Timms, J. E. Garber, C. Herold, L. Ellisen, J. Krejdovsky, K. DeLeonardis, K. Sedgwick, K. Soltis, B. Roa, R. J. Wenstrup and A. R. Hartman. (January 2015). Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer, 121(1). pp. 25–33. Available:

A. C. Antoniou, W. D. Foulkes and M. A. Tischkowitz. (October 2014). Breast-Cancer Risk in Families with Mutations in PALB2. N Engl J Med. 371(17). pp.1651-1652. Available:

B. Decker, J. Allen, C. Luccarini, K. A. Pooley, M. Shah, M. K. Bolla, Q. Wang, S. Ahmed, C. Baynes, D. M. Conroy, J. Brown, R. Luben, E. A. Ostrander, P. D. Pharoah, A. M. Dunning and D. F. Easton (November 2017). Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. J Med Genet. 54(11). pp. 732–741. Available:

A. Desrichard, Y. Bidet, N. Uhrhammer and Y. Bignon. (November 2011)CHEK2 contribution to hereditary breast cancer in non-BRCAfamilies. Breast Cancer Res. 13(6). Available:

A. W. Kurian, E Hughes, E. A. Handorf, A. Gutin, B. Allen, A. R. Hartman and M. J. Hall. (June 2017). Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women. JCO Precis Oncol, 1. pp. 1-12. DOI: 10.1200/po.16.00066.

A. Venkateshwari, D. W. Clark, P. Nallari, C. Vinod, T. Kumarasamy, G. Reddy, A. Jyothy, M. V. Kumar, R. Ramaiyer and K. Palle. (March 2017). BRIP1/FANCJMutation Analysis in a Family with History of Male and Female Breast Cancer in India. J Breast Cancer. 20(1). pp.104–107.

K. Heikkinen, K. Rapakko, S. H. Karppinen, H Erkko, S. Knuutila, T. Lundán, A. Mannermaa, A. L. Børresen-Dale, A. Borg, R. B. Barkardottir, J. Petrini, and R. Winqvist (August 2006). RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis, 27(8) pp. 1593–1599. Available:

F. S. Hilbers, J. T. Wijnen, N. Hoogerbrugge, J. C. Oosterwijk, M. J. Collee, P. Peterlongo, P. Radice, S. Manoukian, I. Feroce, F. Capra, F. J. Couch, X. Wang, L. Guidugli, K. Offit, S. Shah, I. G. Campbell, E. R. Thompson, P. A. James, A. H. Trainer, J. Gracia, J Benitez, C. J. van Asperen and P. Devilee. (October 2012). Rare variants in XRCC2 as breast cancer susceptibility alleles. J Med Genet. 49(10). pp. 618-20. Available:

R. Das, S. Kundu, S. Laskar, Y. Choudhury and S. K. Ghosh. (July 2018). Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer. DNA Repair(Amst). 66-67. pp. 50-63. Available:

N. Mavaddat, A. C. Antoniou, D. F. Easton and M. Garcia-Closas. (June 2010). Genetic susceptibility to breast cancer. Mol Oncol. 4(3). pp. 174-191. Available:


Download data is not yet available.


How to Cite
Fairoosa, P., & Witharana, C. (2020). Gene Mutations in Hereditary Breast Cancer- A Review. European Journal of Medical and Health Sciences, 2(3).