Frequency and spectrum of CHEK2 variants in a large Brazilian set of germline-tested patients.
Authors: Santana Thaiana Aragao , de Bustamante Fernandes Carolina , Silva Ana Carolina Branco Neves , Rego Fernanda Orpinelli Ramos do , Christtanini Koyama Fernanda , Testa Galindo Layla , Tiaki Uehara Daniela , Costa e Silva Matheus , Souto Andreza Karine , de Carvalho Oliveira Leandro Jonata , Konzen Daniele , Landeiro Luciana , de Oliveira Nascimento Ivana Lucia , Lima Bulcão Marcela , Azevedo Renata Gondim Meira Velame de , Farias João Paulo Gonzaga de , Ferrari Bruno Lemos , Zalis Mariano , Dienstmann Rodrigo , Garicochea Bernardo 
Published: June 2023

e22539 Background: CHEK2 is one of the most commonly affected genes in different cancers. P/LP variants can display differences in phenotype and in penetrance in cancer families. Some of the most frequently described variants largely vary from population to population. CHEK2 variants are distributed in the whole gene sequence and it seems that some functional areas can be critical. Additionally, a significant number of variants detected in CHEK2 are classified as VUS and require appropriate functional testing for accurate classification. Therefore, we decided to contribute with databases presenting the largest cohort of CHEK2 P/LP and VUS detected through NGS panels in many cancer centers throughout Brazil. Methods: We conducted a retrospective cohort study including CHEK2 variant carriers identified by genetic testing ordered by Grupo Oncoclinicas health care professionals from 2017 to 2022. Primary endpoint was to describe the prevalence of CHEK2 P/LP and VUS and variants categories as well as sex at birth, age at diagnosis, phenotype and geographic distribution. Results: A total of 207 carriers of CHEK2 variants were identified, with 96 (46%) classified as P/LP and 111 (54%) as VUS. Majority of patients were female (88%), with median age at diagnosis of 45 years for those with P/LP variants. The most observed phenotype was breast cancer (125 cases, 60%), followed by prostate (11.5%), ovarian (7%), thyroid (2%) and kidney cancer (1%). Approximately 25% of patients either had a less common type of cancer, lacked a reported cancer diagnosis, or did not provide information regarding the specific type of cancer. The most frequent variants were p.Arg117Gly (14.5%) and p.Ile157Thr (7.2%). Despite being predominantly described in association with breast cancer in North American, c.1100del variant was the third most frequent in our population, occurring in 14 (6.7%) cases, with breast cancer being its slightly more common phenotype 57.1% (8/14 patients). Among p.Arg117Gly carriers, breast cancer was also the most frequently observed phenotype, accounting for 23 out of 30 patients (76.7%), whereas among p.Ile157Thr carriers, it represented a lower proportion of cases, 5 out of 15 patients (33.3%). Of the 207 patients, 58.4% were from the Southeast region and 25% were from the South region. Conclusions: This study is the largest cohort of germinative CHEK2 variants reported in Brazil, which showed p.Arg117Gly and p.Ile157Thr to be the most prevalent variants and breast cancer to be the most common phenotype, particularly among carriers of the p.Arg117Gly variant. The significant number of VUS identified, however, represents a challenge for genetic counseling in developing countries and highlights the need for further research to classify these variants as well as for functional testing to improve understanding about their association with cancer.