Prevalence of Variants of Uncertain Significance in Patients Undergoing Genetic Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2023 Dec 23

PMID 38136308

Authors

Pavlina Chrysafi

Chinmay T Jani

Margaret Lotz

Omar Al Omari

Harpreet Singh

Katherine Stafford

Lipisha Agarwal

Arashdeep Rupal

Abdul Qadir Dar

Abby Dangelo

Prudence Lam

Affiliations

Soon will be listed here.

Abstract

Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS) are the most common inherited cancer syndromes identified with genetic testing. Testing, though, commonly reveals variants of uncertain significance (VUSs). This is a retrospective observational study designed to determine the prevalence of pathogenic mutations and VUSs in patients tested for HBOC and/or LS and to explore the characteristics of the VUS population. Patients 18-80 years old that met NCCN criteria for HBOC and/or LS genetic screening were tested between 2006 and 2020 at Mount Auburn Hospital in Cambridge, Massachusetts. A total of 663 patients were included in the study, with a mean age of 50 years old and 90% being females. Pathogenic mutations were identified in 12.5% and VUSs in 28.3%. VUS prevalence was associated with race (-value = 0.019), being particularly higher in Asian populations. Patients with a personal history of breast cancer or family history of breast or ovarian cancer were more likely to have a VUS (personal breast: OR: 1.55; CI: 1.08-2.25; family breast: OR: 1.68; CI: 1.08-2.60, family ovarian OR: 2.29; CI: 1.04-5.45). In conclusion, VUSs appear to be detected in almost one third patients tested for cancer genetic syndromes, and thus future work is warranted to determine their significance in cancer development.

Citing Articles

Regional Hereditary Cancer Program in Chile: A scalable model of genetic counseling and molecular diagnosis to improve clinical outcomes for patients with hereditary cancer across Latin America.

Landeros N, Vargas-Roig L, Denita S, Mampel A, Hasbun R, Araya H Biol Res. 2024; 57(1):99.

PMID: 39710803 PMC: 11664851. DOI: 10.1186/s40659-024-00579-x.

Genomic landscape of cancer in racially and ethnically diverse populations.

Thomas C, Peters U Nat Rev Genet. 2024; .

PMID: 39609636 DOI: 10.1038/s41576-024-00796-w.

The Role of Health Literacy in Skin Cancer Preventative Behavior and Implications for Intervention: A Systematic Review.

Chang R, Yen H, Heskett K, Yen H J Prev (2022). 2024; 45(6):957-972.

PMID: 39110380 DOI: 10.1007/s10935-024-00795-x.

Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes.

Fernandez Acenero M, Diaz Del Arco C Curr Issues Mol Biol. 2024; 46(7):6440-6471.

PMID: 39057027 PMC: 11275188. DOI: 10.3390/cimb46070385.

References

Iqbal J, Ragone A, Lubinski J, Lynch H, Moller P, Ghadirian P . The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2012; 107(12):2005-9. PMC: 3516682. DOI: 10.1038/bjc.2012.483. View

Clarke J, Magoon S, Forghani I, Alessandrino F, DAmato G, Jonczak E . Radiologic screening and surveillance in hereditary cancers. Eur J Radiol Open. 2022; 9:100422. PMC: 9301608. DOI: 10.1016/j.ejro.2022.100422. View

Abdel-Razeq H, Tamimi F, Abujamous L, Abdel-Razeq R, Abunasser M, Edaily S . Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives. Front Oncol. 2022; 12:673094. PMC: 8989924. DOI: 10.3389/fonc.2022.673094. View

Samuel D, Diaz-Barbe A, Pinto A, Schlumbrecht M, George S . Hereditary Ovarian Carcinoma: Cancer Pathogenesis Looking beyond and . Cells. 2022; 11(3). PMC: 8834207. DOI: 10.3390/cells11030539. View

Caswell-Jin J, Gupta T, Hall E, Petrovchich I, Mills M, Kingham K . Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk. Genet Med. 2017; 20(2):234-239. DOI: 10.1038/gim.2017.96. View

Khandakji M, Habish H, Abdulla N, Kusasi S, Abdou N, Al-Mulla H . -specific machine learning model predicts variant pathogenicity with high accuracy. Physiol Genomics. 2023; 55(8):315-323. PMC: 10393322. DOI: 10.1152/physiolgenomics.00033.2023. View

Woods N, Baskin R, Golubeva V, Jhuraney A, De-Gregoriis G, Vaclova T . Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. NPJ Genom Med. 2017; 1. PMC: 5539989. DOI: 10.1038/npjgenmed.2016.1. View

Stolarova L, Kleiblova P, Janatova M, Soukupova J, Zemankova P, Macurek L . Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate. Cells. 2020; 9(12). PMC: 7763663. DOI: 10.3390/cells9122675. View

Rahner N, Steinke V . Hereditary cancer syndromes. Dtsch Arztebl Int. 2009; 105(41):706-14. PMC: 2696972. DOI: 10.3238/arztebl.2008.0706. View

10.

Ready K, Gutierrez-Barrera A, Amos C, Meric-Bernstam F, Lu K, Hortobagyi G . Cancer risk management decisions of women with BRCA1 or BRCA2 variants of uncertain significance. Breast J. 2011; 17(2):210-2. DOI: 10.1111/j.1524-4741.2010.01055.x. View

11.

Segev Y, Iqbal J, Lubinski J, Gronwald J, Lynch H, Moller P . The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: an international prospective cohort study. Gynecol Oncol. 2013; 130(1):127-31. DOI: 10.1016/j.ygyno.2013.03.027. View

12.

Monteiro A, Bouwman P, Kousholt A, Eccles D, Millot G, Masson J . Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation. J Med Genet. 2020; 57(8):509-518. PMC: 7390672. DOI: 10.1136/jmedgenet-2019-106368. View

13.

Kurian A, Ward K, Abrahamse P, Bondarenko I, Hamilton A, Deapen D . Time Trends in Receipt of Germline Genetic Testing and Results for Women Diagnosed With Breast Cancer or Ovarian Cancer, 2012-2019. J Clin Oncol. 2021; 39(15):1631-1640. PMC: 8274804. DOI: 10.1200/JCO.20.02785. View

14.

Buerki N, Gautier L, Kovac M, Marra G, Buser M, Mueller H . Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosomes Cancer. 2011; 51(1):83-91. DOI: 10.1002/gcc.20935. View

15.

Stolarova L, Kleiblova P, Zemankova P, Stastna B, Janatova M, Soukupova J . ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. Clin Cancer Res. 2023; 29(16):3037-3050. PMC: 10425727. DOI: 10.1158/1078-0432.CCR-23-0212. View

16.

Makhnoon S, Shirts B, Bowen D . Patients' perspectives of variants of uncertain significance and strategies for uncertainty management. J Genet Couns. 2019; 28(2):313-325. DOI: 10.1002/jgc4.1075. View

17.

Weiss J, Gupta S, Burke C, Axell L, Chen L, Chung D . NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021. J Natl Compr Canc Netw. 2021; 19(10):1122-1132. DOI: 10.1164/jnccn.2021.0048. View

18.

Sheehan M, Heald B, Yanda C, Kelly E, Grobmyer S, Eng C . Investigating the Link between Lynch Syndrome and Breast Cancer. Eur J Breast Health. 2020; 16(2):106-109. PMC: 7138356. DOI: 10.5152/ejbh.2020.5198. View

19.

Samadder N, Giridhar K, Baffy N, Riegert-Johnson D, Couch F . Hereditary Cancer Syndromes-A Primer on Diagnosis and Management: Part 1: Breast-Ovarian Cancer Syndromes. Mayo Clin Proc. 2019; 94(6):1084-1098. DOI: 10.1016/j.mayocp.2019.02.017. View

20.

Malander S, Rambech E, Kristoffersson U, Halvarsson B, Ridderheim M, Borg A . The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. Gynecol Oncol. 2005; 101(2):238-43. DOI: 10.1016/j.ygyno.2005.10.029. View