Coinheritance of pathogenic variants in ATM and BRCA2 in families with multiple cancers: a case series

Abstract

Abstract Purpose. Pathogenic variants (PVs) in BRCA2 and ATMgenes have been linked to an increased risk of various cancers. BRCA2and ATM are part of the homologous recombination pathway, but the tumor risk in patients with simultaneous PVs in both genes remains largely unknown. In this study we describe four patients from three families with multiple cancers who coinherited PVs in BRCA2 and ATM genes. Methods. PVs in the patients were identified using NGS sequencing of the DNA and were confirmed by Sanger sequencing. Results. The first family included a 67-year-old male with kidney, prostate, and pancreatic adenocarcinomas, and his daughter diagnosed with breast cancer at 29 years. In the second family, a 28-year-old female had breast cancer, while a male from the third family was diagnosed with prostate cancer at the age of 49, gastric cancer one year later and pancreatic cancer at 64. The three identified BRCA2 PVs were nonsense variants previously described as pathogenic, leading to a severely truncated or absent protein due to nonsense-mediated mRNA decay. Two of the ATM variants were previously reported as pathogenic, while the third one affects a conserved splice site. Conclusions. The early age of diagnosis and the development of multiple cancers in the reported patients indicate a very high risk of cancer in double heterozygous patients, carrying PVs in the BRCA2 and ATM genes.