New Insights Into c.815_824dup Pathogenic Variant of BRCA1 in Inherited Breast Cancer: A Founder Mutation of West African Origin

Abstract

Founder mutations have been reported in BRCA1 and BCRA2 in different ethnic groups with inherited breast cancer. Testing of targeted mutations in specific populations is important for cancer prevention in mutation carriers. In Sub-Saharan Africa, only a few studies have reported specific founder mutations in inherited breast cancer. The pathogenic variant c.815_824dup of BRCA1 has been reported as the most frequent among African American populations with inherited breast cancer and was supposed to have a West African origin. Recent report from Senegal identified this variant in women with inherited breast cancer at the highest frequency ever reported. The variant was linked to a common haplotype confirming its founder effect in West Africa. In this article, we review the mutation history of c.815_824dup and discuss how it spread out of Africa through the transatlantic slave trade.

Genetic contribution of breast cancer genes in women of black African origin

“…Other reported studies focused on BRCA1 and BRCA2 genes in limited families or sporadic cases. This is the case for South Africa, Senegal, Burkina Faso and Mauritania (Levy et al, 2011;Diop et al, 2021;Ouedraogo et al, 2022;Van der Merwe et al, 2022) (Table 1).…”

“…Most of them focused on the major genes BRCA1 and BRCA2 , and highlighted strong genetic contribution of BRCA1 c.814_824dup10 in Senegal (56%) and Mauritania (34.2%). The variant was reported with high allelic frequency, respectively 30% and 4.7% in Senegal and Mauritania with a founder effect ( Diop et al, 2021 ; Brahim et al, 2022 ). In South Africa BRCA2 gene had the highest contribution (11.8%) with identification of 2 black founder variants BRCA2 c.582G>A and BRCA2 c.5771_5774del.…”

“…Oosthuizen et al (2020) Data from Burkina Faso did not show strong genetic contribution of BRCA genes (Table 2). In light of these studies, it appears that genetic contribution to BC is heterogeneous between SSA countries and accounts for 12.7%-56% of BC cases (Diop et al, 2021;Ahearn et al, 2022). The 4 major genes contributing to BC are BRCA1, BRCA2, PALB2, and TP53 while population specific major genes have been raised.…”

Gynecologic Care of Black Breast Cancer Survivors

“…Testing results among Black communities may reflect similar prevalence of germline mutations (such as BRCA1/2) as compared to White communities [ 134 – 136 ], with the exception of the BRCA1 c.815_824dup founder mutation noted particularly among Black populations in the Southern U.S. and Caribbean [ 137 , 138 ]. However, due to lack of inclusion in genome-wide association studies (GWAS) [ 139 ] and genomic research as a whole, Black people are more likely to have variants of unknown or uncertain significance (VUS) when undergoing genetic testing [ 140 – 146 ].…”