Limited versus expanded multigene germline genetic testing among adolescents and young adults (AYA) with breast cancer.

10588 Background: In low- and middle-income countries, like ours, breast cancer is diagnosed mostly in younger women. With a median age of 50-52 years, breast cancer is diagnosed at least 10 years younger than in Western societies. Though most breast cancer cases are sporadic, 5-10% of cases are hereditary and mostly related to BRCA1 or BRCA2 variants. However, the widespread use of genetic testing, mutations other than BRCA1/2 are currently detected, the clinical importance of which is questionable. In this paper, we aim to study the prevalence and pattern of pathogenic/likely pathogenic (P/LP) variants among adolescents and young adults (AYA). Methods: Blood samples of patients with breast cancer diagnosed at age 39 years or younger were obtained for DNA extraction and sequencing. Mutations were classified as benign/likely benign (non-carrier), P/LP (carrier), and variant of uncertain significance (VUS). At the initial phases of testing, patients were tested for only BRCA1 and BRCA2 (n = 415), then PALB2 was added (n = 145). With availability and affordability of germline genetic testing, 267 patients were tested utilizing an 84-gene panel before we settled on a 21-gene panel (n = 897). Testing was done at reference referral labs. All patients were counselled by a genetic counsellor before and after testing. Results: During the study period, a total of 1,724 patients with breast cancer diagnosed at age 18-39 had germline genetic testing and were included in the analysis. Majority (n = 1,530, 88.8%) were Jordanian, while the rest were non-Jordanian Arab. Median (range) age was 35 (15-39) years, and except for 6 patients, all were female. Among the whole group, 262 (15.2%) had pathogenic or likely pathogenic (P/LP) variants and were mostly BRCA2 (n = 121, 46.2%) and BRCA1 (n = 76, 29.0%). Other variants include TP53 (n = 15, 5.7%), ATM (n = 12, 4.6%), CHEK2 (n = 11, 4.2 %) and PALB2 (n = 8, 3.1%). Rate of P/LP variants was significantly higher among patients younger than 30 years (23.6%) compared to a rate of 13.8% among older ones aged 30-39 years, p = 0.0001. Rates of P/LP variants were higher in patients tested with the 84-multigene panel (17.9%) compared to those who were tested with the 21-MGP (15.5%) or BRCA1/2 with or without PALB2 (13.6%). VUS rates were significantly higher with expanded gene testing; 54.7% with 84-gene, 22.5% with 21-gene and less than 10% with limited gene testing, p < 0.0001. Limiting testing to BRCA1, BRCA2, PALB2, CHEK2, TP53 and ATM would include 92.7% (n = 243) of all P/L variants. The remaining 19 (7.3%) are variants of low penetrance. Conclusions: The rate of P/LP variants in AYA patients, particularly those under 30 years, with breast cancer is higher than what has been previously observed in older patients. Expanding genetic testing beyond BRCA1, BRCA2, PALB2, CHEK2, ATM , and TP53 in this age group leads to a lower yield and a significantly higher proportion of VUS.