Abstract
Background
Mutations in the BRCA1 and BRCA2 genes constitute a risk factor for breast cancer development. BRCA mutation research has been an active field since the discovery of the genes, and new mutations in both genes are constantly described and classified according to several systems.
Aim
We intend to provide an overview of the current state of BRCA1 and BRCA2 mutation description and classification. We wanted to know whether there was a trend towards a more frequently described mutation type and what the proportion of pathogenic mutations was.
Results
We found that, although new mutations are described each year as reflected in current database records, very few of them are reported in papers. Classification systems are highly heterogeneous and a consensus among them is still under development. Regarding their function, a large number of mutations are yet to be analyzed, a very complex task, due to the great number of possible variations and their diverse effect in the BRCA gene functions. After individual analysis, many variants of unknown significance turn out to be pathogenic, and many can disrupt interactions with other proteins involved in mechanisms such as DNA damage repair pathways. Recent data suggest that looking for mutation patterns or combinations would shed a wider light on BRCA-derived cancer susceptibility in the upcoming years.
Similar content being viewed by others
References
BIC Consortium (1995) Breast cancer information core. https://research.nhgri.nih.govprojectsbic
Landrum MJ, Lee JM, Benson M et al (2016) ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 44:D862–D868. https://doi.org/10.1093/nar/gkv1222
Dunnen den J, Antonarakis E (2001) Nomenclature for the description of human sequence variations. Hum Genet 109:121–124. https://doi.org/10.1007/s004390100505
Antonarakis SE (1998) Recommendations for a nomenclature system for human gene mutations. Hum Mutat 11:1–3. https://doi.org/10.1002/(SICI)1098-1004(1998)11:1%3C1::AID-HUMU1%3E3.0.CO;2-O
Capalbo C, Ricevuto E, Vestri A et al (2006) BRCA1 and BRCA2 genetic testing in Italian breast and/or ovarian cancer families: mutation spectrum and prevalence and analysis of mutation prediction models. Ann Oncol 17:vii34–vii40. https://doi.org/10.1093/annonc/mdl947
Giannini G, Capalbo C, Ristori E et al (2006) Novel BRCA1 and BRCA2 germline mutations and assessment of mutation spectrum and prevalence in Italian breast and/or ovarian cancer families. Breast Cancer Res Treat 100:83–91. https://doi.org/10.1007/s10549-006-9225-9
Eccles DM, Mitchell G, Monteiro ANA et al (2015) BRCA1 and BRCA2 genetic testing—pitfalls and recommendations for managing variants of uncertain clinical significance. Ann Oncol 26:2057–2065. https://doi.org/10.1093/annonc/mdv278
Lincoln SE, Yang S, Cline MS et al (2017) Consistency of BRCA1 and BRCA2 variant classifications among clinical diagnostic laboratories. JCO Precis Oncol 1:721–722. https://doi.org/10.1038/gim.2016.196
Chenevix-Trench G, Milne RL, Antoniou AC et al (2007) An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 9:104. https://doi.org/10.1186/bcr1670
Spurdle AB, Healey S, Devereau A et al (2012) ENIGMA—evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum Mutat 33:2–7. https://doi.org/10.1002/humu.21628
Forbes S, Clements J, Dawson E et al (2006) COSMIC 2005. Br J Cancer 94:318–322. https://doi.org/10.1038/sj.bjc.6602928
2006 Human Variome Project, Appelbe W, Auerbach AD et al (2007) Recommendations of the 2006 human variome project meeting. In: Nat. Genet. pp 433–436
Couch FJ, Weber BL (1996) Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Hum Mutat 8:8–18. https://doi.org/10.1002/humu.1380080102
Puget N, Torchard D, Serova-Sinilnikova OM et al (1997) A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res 57:828–831
Mazoyer S (2005) Genomic rearrangements in theBRCA1 andBRCA2 genes. Hum Mutat 25:415–422. https://doi.org/10.1002/humu.20169
Borg A, Haile RW, Malone KE et al (2010) Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat 31:E1200–E1240. https://doi.org/10.1002/humu.21202
Szabo CI, King MC (1997) Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60:1013–1020
Fackenthal JD, Olopade OI (2007) Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7:937–948. https://doi.org/10.1038/nrc2054
Ewald IP, Ribeiro PLI, Palmero EI et al (2009) Genomic rearrangements in BRCA1 and BRCA2: a literature review. Genet Mol Biol 32:437–446. https://doi.org/10.1590/S1415-47572009005000049
Karami F, Mehdipour P (2013) A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. Biomed Res Int 2013:928562. https://doi.org/10.1155/2013/928562
Rebbeck TR, Friebel TM, Friedman E et al (2018) Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat 39:593–620. https://doi.org/10.1002/humu.23406
Maillet P, Chappuis PO, Khoshbeen-Boudal M et al (2006) Twenty-three novel BRCA1 and BRCA2 sequence variations identified in a cohort of Swiss breast and ovarian cancer families. Cancer Genet Cytogenet 169:62–68. https://doi.org/10.1016/j.cancergencyto.2006.03.010
Lee MS, Green R, Marsillac SM et al (2010) Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res 70:4880–4890. https://doi.org/10.1158/0008-5472.CAN-09-4563
Steffensen AY, Dandanell M, Jønson L et al (2014) Functional characterization of BRCA1 gene variants by mini-gene splicing assay. Eur J Hum Genet 22:1362–1368. https://doi.org/10.1038/ejhg.2014.40
Easton DF, Deffenbaugh AM, Pruss D et al (2007) A systematic genetic assessment of 1433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet 81:873–883. https://doi.org/10.1086/521032
Vallée MP, Francy TC, Judkins MK et al (2012) Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs. Hum Mutat 33:22–28. https://doi.org/10.1002/humu.21629
Kurz EU, Lees-Miller SP (2004) DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair 3:889–900. https://doi.org/10.1016/j.dnarep.2004.03.029
Christou C, Kyriacou K (2013) BRCA1 and its network of interacting partners. Biology 2:40–63. https://doi.org/10.3390/biology2010040
Takaoka M, Miki Y (2017) BRCA1 gene: function and deficiency. Int J Clin Oncol 23:36–44. https://doi.org/10.1007/s10147-017-1182-2
Knijnenburg TA, Wang L, Zimmermann MT et al (2018) Genomic and molecular landscape of DNA Damage repair deficiency across the cancer genome atlas. Cell Rep 23:239–254.e6. https://doi.org/10.1016/j.celrep.2018.03.076
Frazer KA, Murray SS, Schork NJ, Topol EJ (2009) Human genetic variation and its contribution to complex traits. Nat Rev Genet 10:241–251. https://doi.org/10.1038/nrg2554
Di Giacomo D, Gaildrat P, Abuli A et al (2013) Functional Analysis of a Large set of BRCA2exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements. Hum Mutat 34:1547–1557. https://doi.org/10.1002/humu.22428
Soukarieh O, Gaildrat P, Hamieh M et al (2016) Exonic splicing mutations are more prevalent than currently estimated and can be predicted by using in silico tools. PLoS Genet 12:e1005756–e1005726. https://doi.org/10.1371/journal.pgen.1005756
Wang Y, Bernhardy AJ, Cruz C et al (2016) The BRCA1-∆11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin. Cancer Res 76:2778–2790. https://doi.org/10.1158/0008-5472.CAN-16-0186
Bachelier R, Dalla Venezia N, Mazoyer S et al (2000) Differential expression and subcellular localization of murine BRCA1 and BRCA1-delta 11 isoforms in murine and human cell lines. Int J Cancer 88:519–524
Wang X, Wang R-H, Li W et al (2004) Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure. J Biol Chem 279:29606–29614. https://doi.org/10.1074/jbc.M312279200
Elstrodt F, Hollestelle A, Nagel JHA et al (2006) BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants. Cancer Res 66:41–45. https://doi.org/10.1158/0008-5472.CAN-05-2853
Doss CGP, Nagasundaram N (2014) An integrated in silico approach to analyze the involvement of single amino acid polymorphisms in FANCD1/BRCA2-PALB2 and FANCD1/BRCA2-RAD51 complex. Cell Biochem Biophys 70:939–956. https://doi.org/10.1007/s12013-014-0002-9
Kean S (2014) Breast cancer. The “other” breast cancer genes. Science 343:1457–1459. https://doi.org/10.1126/science.343.6178.1457
Antoniou AC, Casadei S, Heikkinen T et al (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497–506. https://doi.org/10.1056/NEJMoa1400382
Song H, Dicks E, Ramus SJ et al (2015) Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol 33:2901–2907. https://doi.org/10.1200/JCO.2015.61.2408
Sánchez-Bermúdez AI, Sarabia-Meseguer MD, García-Aliaga Á et al (2018) Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). Eur J Med Genet 61:355–361. https://doi.org/10.1016/j.ejmg.2018.01.015
Funding
This study was funded by DGAPA-PAPIIT, Universidad Nacional Autónoma de México with Grant Number IA201216, awarded to E.L-U. and grant number IN207216, awarded to C.P-P.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Electronic supplementary material
Below is the link to the electronic supplementary material.
10549_2018_4986_MOESM1_ESM.xlsx
Journal articles published between 1994 and 2017 that describe new BRCA 1 and BRCA 2 mutations. Supplementary material 1 (XLSX 40 KB)
10549_2018_4986_MOESM2_ESM.xlsx
Journal articles published between 1994 and 2017 that describe cancer risk analysis of BRCA 1 and BRCA 2 VUS. Supplementary material 2 (XLSX 20 KB)
Rights and permissions
About this article
Cite this article
López-Urrutia, E., Salazar-Rojas, V., Brito-Elías, L. et al. BRCA mutations: is everything said?. Breast Cancer Res Treat 173, 49–54 (2019). https://doi.org/10.1007/s10549-018-4986-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-018-4986-5