Background: Genetic testing for breast cancer-related genes can have implications for diagnosis, treatment, and management of breast cancer. The identification of the variants causing the disease would guide the examination and diagnosis of the at-risk relatives. The purpose of this study was to identify the frequency of pathogenic or likely pathogenic variants associated with hereditary breast and ovarian cancer in Korean patients. In this study, we conducted a multigene panel containing 23 genes with high and middle penetrance rates in hereditary breast and ovarian cancer.

Methods: A multigene panel was performed on 382 patients who agreed to this study and visited the genetic counselling clinic at the National Cancer Center of Korea, between October 2016 and 2018 July. For variants classification, we examined Sanger sequencing, family history, and the clinical pathological characteristics for patients according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. We also measured the expression of alternative spliced transcripts by conducting quantitative real-time PCR (qRT-PCR) to investigate the splice donor variants interpreted with pathogenic or likely pathogenic.

Results: We confirmed that 42 patients (11.00%) had 23 pathogenic or 10 likely pathogenic variants for the high and middle penetrance genes such as BRCA1, BRCA2, ATM, CHEK2, MLH1, PALB2, TP53, BRIP1 and PMS2, except for heterozygous MUTYH mutation carriers. The number of mutation careers was evaluated as follows: BRCA1 in 9 patients, BRCA2 in 18 patients, ATM in 2 patients, CHEK2 in 4 patients, MLH1 in 1 patient, PALB2 in 4 patients, TP53 in 1 patient and PMS2 in 1 patient. Two patients had 2 pathogenic or likely pathogenic variants for other genes; BRCA1/BRIP1 and BRCA2/CHEK2. All of these variants were validated by Sanger sequencing. The mRNA level of CHEK2 or PALB2 genes was further reduced in the patients with the splice donor variants compared to controls. The patients with a family history were advised to follow targeted screenings according to the National Comprehensive Cancer Network (NCCN) guidelines so that early detection of cancer and reduction of risk factors can be achieved.

Conclusions: Multigene panels including high and middle penetrance rate genes will provide important information for patients with a family history of cancer. However, functional studies are needed to determine potential clinical impact of these variants. Thus, we are conducting the additional functional assays to resolve the questions for these variants (This study was supported by National Cancer Center, Korea, 1710172)

Citation Format: Jin-Sun Ryu, Eun Hae Cho, Kyong-Ah Yoon, Eun-Gyeong Lee, Eun-Sook Lee, Sun-Young Kong. Identification of high and middle penetrance pathogenic variants in patients with hereditary breast/ovarian cancer by multigene panel analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1405.