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The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients



Hereditary cancer risk syndromes are caused by germline variants, commonly in tumor suppressor genes. Most studies on hereditary cancer have been conducted in white populations. We report the largest study in Brazilian individuals with multiple ethnicities. We genotyped 1682 individuals from all country regions with Next-generation sequencing (NGS) panels. Most were women with a personal/family history of cancer, mostly breast and ovarian. We identified 321 pathogenic/likely pathogenic (P/LP) variants in 305 people (18.1%) distributed among 32 genes. Most were on BRCA1 and BRCA2 (129 patients, 26.2% and 14.3% of all P/LP, respectively), MUTYH (42 monoallelic patients, 13.1%), PALB2 (25, 7.8%), Lynch syndrome genes (17, 5.3%), and TP53 (17, 5.3%). Transheterozygosity prevalence in our sample was 0.89% (15/1682). BRCA1/BRCA2 double heterozygosity rate was 0.78% (1/129) for BRCA variants carriers and 0.06% (1/1682) overall. We evaluated the performance of the genetic testing criteria by NCCN and the Brazilian National Health Agency (ANS). The inclusion criteria currently used in Brazil fail to identify 17%–25% of carriers of P/LP variants in hereditary cancer genes. Our results add knowledge on the Brazilian spectrum of cancer risk germline variants, demonstrate that large multigene panels have high positivity rates, and indicate that Brazilian inclusion criteria for genetic testing should be improved.

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Fig. 1: Variants profiles.
Fig. 2: Transheterozygotes heatmap.

Data availability

All data generated or analysed during this study are included in this published article and its Supplementary Information Files.


  1. Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene. 2004;23:6445–70.

    CAS  Article  Google Scholar 

  2. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  3. Biesecker LG, Harrison SM. ClinGen Sequence Variant Interpretation Working G. The ACMG/AMP reputable source criteria for the interpretation of sequence variants. Genet Med. 2018;20:1687–8.

    Article  Google Scholar 

  4. Yoshida R. Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis. Breast Cancer. 2020;28:1167–80.

  5. Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016;18:823–32.

    CAS  Article  Google Scholar 

  6. Neben CL, Zimmer AD, Stedden W, van den Akker J, O’Connor R, Chan RC, et al. Multi-gene panel testing of 23,179 individuals for hereditary cancer risk identifies pathogenic variant carriers missed by current genetic testing guidelines. J Mol Diagn. 2019;21:646–57.

    Article  Google Scholar 

  7. Alemar B, Herzog J, Brinckmann Oliveira Netto C, Artigalás O, Schwartz IVD, Matzenbacher Bittar C, et al. Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet. 2016;209:417–22.

    CAS  Article  Google Scholar 

  8. Dillenburg CV, Bandeira IC, Tubino TV, Rossato LG, Dias ES, Bittelbrunn AC, et al. Prevalence of 185delAG and 5382insC mutations in BRCA1, and 6174delT in BRCA2 in women of Ashkenazi Jewish origin in southern Brazil. Genet Mol Biol. 2012;35:599–602.

    CAS  Article  Google Scholar 

  9. Cipriano NM Jr., de Brito AM, de Oliveira ES, de Faria FC, Lemos S, Rodrigues AN, et al. Mutation screening of TP53, CHEK2 and BRCA genes in patients at high risk for hereditary breast and ovarian cancer (HBOC) in Brazil. Breast Cancer. 2019;26:397–405.

    Article  Google Scholar 

  10. Okano M, Nomizu T, Tachibana K, Nagatsuka M, Matsuzaki M, Katagata N, et al. The relationship between BRCA-associated breast cancer and age factors: an analysis of the Japanese HBOC consortium database. J Hum Genet. 2021;66:307–14.

    CAS  Article  Google Scholar 

  11. Palmero EI, Carraro DM, Alemar B, Moreira MAM, Ribeiro-Dos-Santos A, Abe-Sandes K, et al. The germline mutational landscape of BRCA1 and BRCA2 in Brazil. Sci Rep. 2018;8:9188.

    Article  Google Scholar 

  12. Rebbeck TR, Friebel TM, Mitra N, Wan F, Chen S, Andrulis IL, et al. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. Breast Cancer Research. 2016;18:112.

  13. Leegte B, van der Hout AH, Deffenbaugh AM, Bakker MK, Mulder IM, ten Berge A, et al. Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations. J Med Genet. 2005;42:e20.

    CAS  Article  Google Scholar 

  14. Lavie O, Narod S, Lejbkowicz F, Dishon S, Goldberg Y, Gemer O, et al. Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population. Ann Oncol. 2011;22:964–6.

    CAS  Article  Google Scholar 

  15. Zuradelli M, Peissel B, Manoukian S, Zaffaroni D, Barile M, Pensotti V, et al. Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics. Breast Cancer Res Treat. 2010;124:251–8.

    CAS  Article  Google Scholar 

  16. Noh JM, Choi DH, Nam SJ, Lee JE, Kim JW, Kim SW, et al. Characteristics of double heterozygosity for BRCA1 and BRCA2 germline mutations in Korean breast cancer patients. Breast Cancer Res Treat. 2012;131:217–22.

    CAS  Article  Google Scholar 

  17. Sokolenko AP, Bogdanova N, Kluzniak W, Preobrazhenskaya EV, Kuligina ES, Iyevleva AG, et al. Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations. Breast Cancer Res Treat. 2014;145:553–62.

    CAS  Article  Google Scholar 

  18. Pern F, Bogdanova N, Schürmann P, Lin M, Ay A, Länger F, et al. Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital-based series of German patients with triple-negative breast cancer. PLoS One. 2012;7:e47993.

    CAS  Article  Google Scholar 

  19. Lindor NM, Smyrk TC, Buehler S, Gunawardena SR, Thomas BC, Limburg P, et al. Multiple jejunal cancers resulting from combination of germline APC and MLH1 mutations. Fam Cancer. 2012;11:667–9.

    Article  Google Scholar 

  20. Grindedal EM, Heramb C, Karsrud I, Ariansen SL, Mæhle L, Undlien DE, et al. Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers. BMC Cancer. 2017;17:438.

    Article  Google Scholar 

  21. Yang S, Axilbund JE, O’Leary E, Michalski ST, Evans R, Lincoln SE, et al. Underdiagnosis of hereditary breast and ovarian cancer in medicare patients: genetic testing criteria miss the mark. Ann Surg Oncol. 2018;25:2925–31.

    Article  Google Scholar 

  22. Alemar B, Gregório C, Herzog J, Matzenbacher Bittar C, Brinckmann Oliveira Netto C, Artigalas O, et al. BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? PLOS ONE. 2017;12:e0187630.

    Article  Google Scholar 

  23. American Society of Clinical Oncology. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol. 1996;14:1730–6. discussion 7-40

    Article  Google Scholar 

  24. Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, et al. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32:833–40.

    Article  Google Scholar 

  25. Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004;91:1580–90.

    CAS  Article  Google Scholar 

  26. Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998;62:145–58.

    CAS  Article  Google Scholar 

  27. Evans DG, Eccles DM, Rahman N, Young K, Bulman M, Amir E, et al. A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet. 2004;41:474–80.

    CAS  Article  Google Scholar 

  28. Teixeira N, Maistro S, Del Pilar Estevez Diz M, Mourits MJ, Oosterwijk JC, Folgueira MAK, et al. Predictability of BRCA1/2 mutation status in patients with ovarian cancer: How to select women for genetic testing in middle-income countries. Maturitas. 2017;105:113–8.

    CAS  Article  Google Scholar 

  29. Achatz MI, Caleffi M, Guindalini R, Marques RM, Nogueira-Rodrigues A, Ashton-Prolla P. Recommendations for advancing the diagnosis and management of hereditary breast and ovarian cancer in Brazil. JCO Glob Oncol. 2020;6:439–52.

    Article  Google Scholar 

  30. Ewald IP, Cossio SL, Palmero EI, Pinheiro M, Nascimento IL, Machado TM, et al. BRCA1 and BRCA2 rearrangements in Brazilian individuals with hereditary breast and ovarian cancer syndrome. Genet Mol Biol. 2016;39:223–31.

    CAS  Article  Google Scholar 

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Correspondence to Jarbas Maciel de Oliveira or João Bosco Oliveira.

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The authors declare no competing interests.

Ethical approval

This project was approved by the Research Ethics Committee of the Institute of Integral Medicine Professor Fernando Figueira (CEP-IMIP) in Recife, Pernambuco and all individuals provided written consent for multi-gene testing (protocol number 29567220.4.1001.0071).

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de Oliveira, J.M., Zurro, N.B., Coelho, A.V.C. et al. The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients. Eur J Hum Genet 30, 818–823 (2022).

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