Abstract 1002: BRCA2, ATM, and POT1 genes mutations in Chilean hereditary gastric cancer families

Abstract The purpose of this study is to describe Chilean families having hereditary Gastric Cancer (GC) presenting pathogenic mutations in BRCA 2 (c.4740_4741dup NP_000050.3:p.Glu1581fs), ATM (c.3381_3384del NP_000042.3:p.Gln1128fs) and Protector of Telomers 1 (POT1, 1087C>T:p.Arg363Ter) genes. Only one hereditary diffuse GC (HDGC) Chilean family with a pathogenic CDH1 mutation has been reported, suggesting a low frequency of pathogenic mutation detection in this population. Whole exome sequencing (WES) was performed using the Agilent SureSelect Human All Exome V7 kit and sequenced in a NovaSeq6000 (Illumina, Inc.) S4 150PE aiming 100x. Alignment and variant calling were performed using Illumina Dragen v3.8. Variant calls were re-calibrated using GATK v4 variant recalibration and annotated with Illumina Nirvana and Annovar. Genotypification of the index patient and their family was performed using KASP-PCR. The index patient having a BRCA2 mutation had metastatic HDGC and his mother had asynchronous breast cancer and GC. The family presenting an ATM gene mutation had three GC-affected subjects, the index patient, and both parents. The index patient of the family having a POT1 mutation presented a CG at 47 yr., and two of her children died of CG at 24 yr. All families show an incomplete penetrance and variable expressivity. We are searching for the second hit in the index patient´s tumor samples. This is the first report of a POT1 gene mutation detected in a hereditary GC. POT1 belongs to the shelterin complex that protects telomeres. This mutation affects the binding to the shelterin complex, and it was previously reported in colorectal cancer. Beca Chile Postdoctorado 74190063, CONICYT-FONDAP 15130011 /ANID-FONDAP APOYO 1523A0008, NIH R01CA223978, R21CA199631, U54CA233306, and P30CA093373. Citation Format: Graciela Adriana Molina Fuentes, Ana Patricia Estrada-Florez, Paul Lott, Osvaldo Torres, Cedric Adelsdorfer, Alejandro H Corvalán, Luis Carvajal-Carmona. BRCA2, ATM, and POT1 genes mutations in Chilean hereditary gastric cancer families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1002.