<em>BRCA1/BRCA2</em> variants of uncertain significance in clinical practice: A case report

Huszno,Joanna; Pigłowski,Wojciech; Mazur,Magdalena; Pamuła‑Piłat,Jolanta; Zajkowicz,Artur; Kierzkowska,Anna Fiszer; Wojciechowska,Małgorzata Oczko

doi:10.3892/mco.2021.2385

BRCA1/BRCA2 variants of uncertain significance in clinical practice: A case report

Authors:
- Joanna Huszno
- Wojciech Pigłowski
- Magdalena Mazur
- Jolanta Pamuła‑Piłat
- Artur Zajkowicz
- Anna Fiszer Kierzkowska
- Małgorzata Oczko Wojciechowska
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Affiliations: Genetic Outpatient Clinic, Maria Sklodowska‑Curie, National Research Institute of Oncology, Gliwice Branch, 44‑100 Gliwice, Poland, The Department of Genetic and Molecular Diagnostics of Cancer, Maria Sklodowska‑Curie, National Research Institute of Oncology, Gliwice Branch, 44‑100 Gliwice, Poland
Published online on: August 31, 2021 https://doi.org/10.3892/mco.2021.2385
Article Number: 222

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Abstract

The influence of BRCA1/2 variants of uncertain significance (VUSs) on the cancer risk and their association with the response to treatment is uncertain. The aim of the present study was to evaluate the role of BRCA VUS in patients with breast cancer. A total of two cases of breast cancer patients with the BRCA VUS were described. The complete coding sequence of BRCA1/2 genes was analyzed from the genomic DNA material by next generation sequencing on the Ion Torrent platform. The presence of c.3454G>A (p.Asp1152Asn) VUS in the BRCA1 gene was reported in a 64‑year‑old woman with invasive breast carcinoma. The characteristics of the breast tumors were the following: moderately differentiated‑intermediate grade (NG‑2 G‑2), HER2 (+), estrogen receptor (ER) (+++), progesterone receptor (PR) (+++), luminal A subtype and pT2 N1a Mx. The second detected VUS was the c.2374T>C (p.Tyr792His) variant in the BRCA2 gene. This variant was reported in a 33‑year‑old woman who was diagnosed with right breast cancer (cT2N1M0). The invasive breast carcinoma was characterized as follows: NG‑2 G‑2, ER (+++), PR (+++), Ki‑67 10%, HER2 (+++) and luminal B subtype. The data demonstrated that patients with VUSs should be managed based on their family history of cancer and clinicopathological characteristics. The clinical significance of the VUS in BRCA1/2 may change over time and reclassification of the variant to ‘pathogenic’ or ‘benign’ should be undertaken. Patients with VUS should be followed up regularly.

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1	Prokopcova J, Kleibl Z, Banwell CM and Pohlreich P: The role of ATM in breast cancer development. Breast Cancer Res Treat. 104:121–128. 2007.PubMed/NCBI View Article : Google Scholar
2	Corso G, Montagna G, Figueiredo J, La Vecchia C, Fumagalli Romario U, Fernandes MS, Seixas S, Roviello F, Trovato C, Guerini-Rocco E, et al: Hereditary gastric and breast cancer syndromes related to CDH1 germline mutation: A multidisciplinary clinical review. Cancers (Basel). 12(1598)2020.PubMed/NCBI View Article : Google Scholar
3	Cybulski C, Wokołorczyk D, Jakubowska A, Huzarski T, Byrski T, Gronwald J, Masojć B, Deebniak T, Górski B, Blecharz P, et al: Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol. 29:3747–3752. 2011.PubMed/NCBI View Article : Google Scholar
4	Evans MK and Longo DL: PALB2 mutations and breast-cancer risk. N Engl J Med. 371:566–568. 2014.PubMed/NCBI View Article : Google Scholar
5	Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS and Eng Ch: Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 18:400–407. 2012.PubMed/NCBI View Article : Google Scholar
6	Lim W, Olschwang S, Keller JJ, Westerman AM, Menko FH, Boardman LA, Scott RJ, Trimbath J, Giardiello FM, Gruber SB, et al: Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology. 126:1788–1794. 2004.PubMed/NCBI View Article : Google Scholar
7	Schon K and Tischkowitz M: Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat. 167:417–423. 2018.PubMed/NCBI View Article : Google Scholar
8	Practice bulletin No. 182 summary. Hereditary breast and ovarian cancer syndrome. Obstet Gynecol. 130:657–659. 2017.PubMed/NCBI View Article : Google Scholar
9	King MC, Marks JH and Mandell JB: New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 302:643–646. 2003.PubMed/NCBI View Article : Google Scholar
10	Toss A, Tomasello Ch, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ and Cortesi L: Hereditary ovarian cancer: Not only BRCA 1 and 2 genes. Biomed Res Int. 2015(341723)2015.PubMed/NCBI View Article : Google Scholar
11	Cheon JY, Mozersky J and Cook-Deegan R: Variants of uncertain significance in BRCA: A harbinger of ethical and policy issues to come? Genome Med. 6(121)2014.PubMed/NCBI View Article : Google Scholar
12	Radice P, De Summa S, Caleca L and Tommasi S: Unclassified variants in BRCA genes: Guidelines for interpretation. Ann Oncol. 22 (Suppl 1):i18–i23. 2011.PubMed/NCBI View Article : Google Scholar
13	Lindor NM, Goldgar DE, Tavtigian SV, Plon SE and Couch FJ: BRCA1/2 sequence variants of uncertain significance: A primer for providers to assist in discussions and in medical management. Oncologist. 18:518–524. 2013.PubMed/NCBI View Article : Google Scholar
14	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, 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 associa-tion for molecular pathology. Genet Med. 17:405–424. 2015.PubMed/NCBI View Article : Google Scholar
15	Bittar CM, Vieira IA, Sabato CS, Andreis TF, Alemar B, Artigalás O, Galvão HCR, Macedo GS, Palmero EI and Ashton-Prolla P: TP53 variants of uncertain significance: Increasing challenges in variant interpretation and genetic counseling. Fam Cancer. 18:451–456. 2019.PubMed/NCBI View Article : Google Scholar
16	Han FF, Guo CL and Liu LH: The effect of CHEK2 variant I157T on cancer susceptibility: Evidence from a meta-analysis. DNA Cell Biol. 32:329–335. 2013.PubMed/NCBI View Article : Google Scholar
17	Boonen RACM, Vreeswijk MPG and van Attikum H: Functional characterization of PALB2 variants of uncertain significance: Toward cancer risk and therapy response prediction. Front Mol Biosci. 7(169)2020.PubMed/NCBI View Article : Google Scholar
18	Abdulrahman AA, Heintzelman RC, Corbman M and Garcia FU: Invasive breast carcinomas with ATM gene variants of uncertain significance share distinct histopathologic features. Breast J. 24:291–297. 2018.PubMed/NCBI View Article : Google Scholar
19	Chern JY, Lee SS, Frey MK, Lee J and Blank SV: The influence of BRCA variants of unknown significance on cancer risk management decision-making. J Gynecol Oncol. 30(e60)2019.PubMed/NCBI View Article : Google Scholar
20	Choi MC: Clinical significance of variants of unknown significances in BRCA genes. J Gynecol Oncol. 30(e80)2019.PubMed/NCBI View Article : Google Scholar
21	NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®). Genetic/familial high-risk assessment: Breast and ovarian. Version 3.2019, 2019.
22	Hansen NT, Brunak S and Altman RB: Generating genome-scale candidate gene lists for pharmacogenomics. Clin Pharmacol Ther. 86:183–189. 2009.PubMed/NCBI View Article : Google Scholar
23	Borg Å, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, et al: 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. 2010.PubMed/NCBI View Article : Google Scholar
24	Stegel V, Krajc M, Zgajnar J, Teugels E, De Grève J, Hočevar M and Novaković S: The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population. BMC Med Genet. 12(9)2011.PubMed/NCBI View Article : Google Scholar
25	Kluska A, Balabas A, Paziewska A, Kulecka M, Nowakowska D, Mikula M and Ostrowski J: New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing. BMC Med Genomics. 8(19)2015.PubMed/NCBI View Article : Google Scholar
26	Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, et al: Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 373:2336–2346. 2015.PubMed/NCBI View Article : Google Scholar
27	Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, et al: Analysis of protein-coding genetic variation in 60,706 humans. Nature. 536:285–291. 2016.PubMed/NCBI View Article : Google Scholar
28	Lu Ch, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, et al: Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 6(10086)2015.PubMed/NCBI View Article : Google Scholar
29	Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, Mierzwa T, Szwiec M, Wiśniowski R, Siolek M, et al: Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat. 108:289–296. 2008.PubMed/NCBI View Article : Google Scholar
30	Kirk R: Surgical oncology: Cancer risk reduction in BRCA mutation carriers. Nat Rev Clin Oncol. 7(609)2010.PubMed/NCBI View Article : Google Scholar
31	Chen H, Wu J, Zhang Z, Tang Y and Li X, Liu S, Cao S and Li X: Association between BRCA status and triple-negative breast cancer: A meta-analysis. Front Pharmacol. 9(909)2018.PubMed/NCBI View Article : Google Scholar