GENOMIC PROFILE OF GENETIC VARIANTS ASSOCIATED WITH HEREDITARY BREAST/ OVARIAN CANCER: EXPERIENCE FROM THE ANALYSIS OF MULTIGENE PANEL TESTING IN ARGENTINA

SOTTILE MAYRA L; REDONDO ANALIA L; GOMEZ LAURA C; MONTES CECILIA; MAMPEL ALEJANDRA; VARGAS ROIG LAURA M

Buenos Aires

Simposio; BUENOS AIRES BREAST CANCER SYMPOSIUM - 2024; 2024

Breast cancer (BC) is a disease with high incidence in Argentina and the leading cause of cancer death in women in ourcountry. Hereditary BC and ovarian cancer (HBOC) are mainly caused by deleterious germline mutations in BRCA1 orBRCA2 genes. However, a number of these cancers are due to germline mutations in other susceptibility genes with lowfrequency or reduced penetrance. We aimed to characterize the frequency of pathogenic (P) and likely pathogenic (LP)variants in HBOC susceptibility genes in the Argentine population. 354 women from Mendoza and Cordoba with earlyonset BC/OC or a family history of cancer were included. Patients were tested using NGS panel containing at least 14high- and moderate-penetrance HBOC genes. P and LP variants were identified in 17.2% (61/354) of cases. Fifty-one ofthese carriers presented a diagnosis of BC (3 with bilateral BC), 5 of OC, and 5 were healthy women. The mean age ofcancer diagnosis was 41.5 years. Thirty (8.5%) patients carry germline P/LP variants in BRCA1/2 and 31 (8.7%) in otherHBOC susceptibility genes. A total of 66 P/LP variants were detected: 30/66 (45.4%) in BRCA1/2, 10 in PALB2 (15.2%),5 in CHEK2 (7.6%), 3 in TP53 (4.5%), 3 in ATM (4.5%), 2 (3%) in RAD51C, MLH1, MUTYH, MITF and PMS2, and 5 inother less frequent genes. Four (0.85%) patients were double heterozygote carriers of germline P/LP variants. The cooccurrence of P/LP variants was identified in the following genes: BRCA2+BARD1, TP53+CDKN2A, MLH1+MITF and BRCA2+CHEK2. In addition, a novel LP variant was detected in BRCA2: c.1744del (p.Thr582LeufsTer2), a frameshiftmutation that introduces a premature stop codon in the protein. Our findings would indicate that multigene panel testinggives more accurate information on cancer risk and thus would allow the implementation of more appropriatesurveillance strategies in germline P/LP variants carriers.