Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient?

Abstract

Background. Germline pathogenic mutations in cancer susceptibility genes result in inherited cancer syndromes. In the Afrikaner population of South Africa (SA), three founder mutations in the BRCA genes that lead to hereditary breast and ovarian cancer syndrome (HBOCS) have been identified. Objectives. To investigate the uptake and type of molecular testing performed on patients for HBOCS, to determine the prevalence of the three Afrikaner founder BRCA mutations as well as non-founder BRCA mutations in the study population, and to analyse the utility of two mutation prediction models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and Manchester scoring method) in assisting with the decision for the most cost-effective testing option. Methods. A retrospective file review was performed on counsellees of self-reported Afrikaner ancestry from Johannesburg, SA (2001 -2014), with a personal or family history of breast and/or ovarian cancer. Demographic and family history information was recorded and Manchester and BOADICEA scores were calculated for each patient. Results. Of 86 unrelated counsellees whose files were reviewed, 54 (62.8%) underwent BRCA genetic testing; 18 (33.3%) tested positive for a mutation, and 14 of these (77.8%) for an Afrikaner founder mutation. Twelve counsellees had the BRCA2 c.7934delG mutation. Four non-founder mutations were identified. BOADICEA scores were significantly higher in counsellees who tested positive for a mutation than in those who tested negative. Conclusions. Founder mutation testing should be performed as a first-line option. BOADICEA is very useful in identifying counsellees at high risk for a BRCA mutation and also assists with the decision to pursue further testing following a negative founder mutation result. These findings assist in guiding an informed genetic counselling service for at-risk individuals with an Afrikaner background.

Novel BRCA2 pathogenic variant c.5219 T > G; p.(Leu1740Ter) in a consanguineous Senegalese family with hereditary breast cancer

“…The BRCA2 pathogenic variants identified in African populations and reported in the literature are summarized in Table 2. Most causal pathogenic variants have been identified in exon 11 [16, 31, 33, 35–37], and are predominantly deletions or duplications. Only a few nucleotide substitutions leading to premature stop codons have been reported.…”

“…(Ile2552Asnfs)16Algeria/Tunisia[35, 46]c.7934delGp. (Arg2645Asnfs)17South Africa[33]c.8817_8820delGAAAp. (Lys2939Asnfs)22Nigeria[37]c.9097dupAp.…”

Monoallelic characteristic-bearing heterozygous L1053X in BRCA2 gene among Sudanese women with breast cancer

“…6448dupTAc. 7934delGFounder-c.5946delTC.8162delGSchoeman M, et al 2013 [58]c.5999del4c.6174delTc.582G > AFrancies FZ, et al 2015 [59]c.5771_5774delTTCAc.5213_5216delCTTAc.8754 + 1G > Ac.9097_9098insAc.4798_4800delAATc.7712A > Gc.9875C > Tc.7934delG founderfounderAfrikaner population of South Africa Seymour HJ, et al2016 [60]c.6621delASouth Africac.6761_6762delTTc.5073dupAMoroccoLAARABI FZ, et al2011 [61]c.3381delT Tazzite A, et al 2012 [62]c.7110delAc.7235insGc.517-1G > Ac.6428 C > A Guaoua S, et al2014 [63]c.745-1G > A Jouhadi H, et al2016 [64]c.5682insATunisia Troudi W, et al 2007 [65]c.1309del4c.-25G > Ac.6301 A > Cc.1595 A > Tc.7242 A > Gc.865 A > Gc.1310_1313del (1538delAAGA) Fourati A, et al 2014 [66]c.-26G > A …”

Editor's Choice

“…', [7] Seymour et al inform us of the presence of three founder mutations in the BRCA genes that occur in the Afrikaner population and lead to hereditary breast and ovarian cancer syndrome (HBOCS). Up to 10% of breast cancer cases are attributable to germline mutations in cancer susceptibility genes, leading to heredi tary syndromes.…”