Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications

Background Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes. Methods Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed. Results Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1-2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36-76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines. Conclusions This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies.

Automated summary

This study identified 11 carriers from four seemingly unrelated Ashkenazi Jewish families who had pathogenic variants in both BRCA1/2 and DNA MMR genes. 73% of the double carriers had cancer, with a range of tumor types and ages at diagnosis. The findings suggest that the phenotype of double carriers is not associated with early disease onset or a more severe phenotype, which may have implications for genetic testing and treatment strategies.