Application of Multilayer Evidence for Annotation of C-Terminal BRCA2 Variants

SIMPLE SUMMARY: The potential pathogenic role of germline BRCA2 c.9976A>T and c.10095delinsGAATTATATCT was evaluated in hereditary breast and ovarian cancer (HBOC) patients by investigating 2491 probands and verified in an independent cohort of 122,209 patients. Although the c.10095delinsGAATTATATCT variant was more prevalent among patients compared to control populations, no increased risk for cancer was found. No association between c.9976A>T and clinicopathological parameters or elevated risk for HBOC cases was detected. However, lung cancer was more prevalent in families carrying c.9976A>T compared to pathogenic BRCA1/BRCA2 carrier families. An increased frequency of pancreatic cancer was found in families where c.9976A>T occurred together with other pathogenic BRCA1 variants. The C-terminal stop codon variants showed no association with other pathogenic BRCA2 variants. No loss of heterozygosity (LOH) in tumor tissue and no allelic imbalance in RNA level were confirmed. The c.9976A>T variant may be considered as a potential risk for lung cancer, and a potential modifying factor in pancreatic cancer when it occurs along with the pathogenic BRCA1 variant, although this observation should be validated in a larger sample cohort. ABSTRACT: The clinical relevance of the BRCA2 C-terminal stop codon variants is controversial. The pathogenic role of the germline BRCA2 c.9976A>T and c.10095delinsGAATTATATCT variants in hereditary breast and ovarian cancer (HBOC) patients was evaluated. An association with clinicopathological parameters was performed in 2491 independent probands diagnosed with HBOC and in 122,209 cancer patients reported earlier. Loss-of-heterozygosity (LOH) in tumor samples and allelic imbalance in RNA extracted from peripheral blood cells were investigated. Neither c.10095delinsGAATTATATCT or c.9976A>T variants showed significant association with clinicopathological parameters or elevated risk for HBOC-associated tumors. Lung cancer was more prevalent in families carrying the c.9976A>T variant compared to pathogenic BRCA1 or BRCA2 carrier families. An increased prevalence of pancreatic cancer was found in families where c.9976A>T occurred together with other pathogenic BRCA1 variants. An increased risk for familial pancreatic, lung and upper aero-digestive tract cancers was confirmed in the validation set. Regarding BRCA2 C-terminal variants, no linkage with other pathogenic BRCA2 variants, no LOH in tumor tissue and no allelic imbalance in RNA level were confirmed. The c.9976A>T variant may be considered as a potential risk for lung cancer, and a potential modifying factor in pancreatic cancer when it occurs along with the pathogenic BRCA1 variant, although this observation should be validated in a larger sample cohort.