Double heterozygous pathogenic variants prevalence in a cohort of patients with hereditary breast cancer

Abstract

Hereditary breast cancer (BC) corresponds to 5% of all BC and a larger parcel of early-onset disease. The incorporation of next-generation sequencing (NGS) techniques reduced the cost of molecular testing and allowed the inclusion of additional cancer predisposition genes in panels that are more comprehensive. This enabled the identification of germline pathogenic variants in carriers and the introduction of risk-reducing strategies. It also resulted in the identification of the co-occurrence of more than one germline pathogenic variant in BC genes in some families. This is a rare event, and there are few reports on its impact on cancer risk. We conducted a single-institution retrospective study in which 1,156 women with early onset BC and/or a family history of cancer were tested by a germline multi-gene hereditary cancer panel. Germline pathogenic variants in high- and/or moderate-penetrance BC genes were identified in 19.5% of the individuals (n = 226). The most frequent variants were found in TP53 (69 of 226; 55 of them represented by p.R337H), BRCA1 (47 of 226), and BRCA2 (41 of 226). Double heterozygous (DH) variants were detected in 14 cases, representing 1.2% of all individuals assessed. There were no significant differences in age of BC onset and risk for bilateral BC in DH carriers when compared with those with one germline variant.

Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand

“…To date, there is limited data on double mutations in cancer patients. One study found double heterozygous variants in 1.2% of hereditary breast cancer patients 37 . However, the exact prevalence is still undetermined.…”

Germline mutations in hereditary breast-ovarian cancer spectrum in Thailand: Results from multi-gene panel testing in 4,567 Thai patients

“…To date, data on concomitant pathogenic variants in cancer patients was limited. One study identi ed double heterozygous variants in 1.2% of hereditary breast cancer patients [34]. However, the exact prevalence is still undetermined.…”

Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients

“…Previously, we reported that early-onset rectal cancer (<40 years) patients exhibited a significantly higher number of germline variants, as well as multiple variants in oncogenes, tumor suppressors, and mismatch repair genes associated with hereditary colorectal cancer [ 35 ]. In early-onset breast cancer, concurrent germline variants of BRCA1 , BRCA2 , PMS2 , and PALB2 were reported [ 36 ]. Analysis of hereditary cancer cases (732 BC patients, 189 CRC patients, and 490 cancer-free elderly controls) revealed that 1% presented concurrent germline pathogenic variants in BRCA1 , BRCA2 , MUTYH , ATM , CHECK2 , NBN , and RAD50 [ 37 ].…”