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

Breast cancer is the leading female cancer in the world in terms of incidence and mortality. In 2012 it was diagnosed in 1.7 million cases with 500,000 deaths [1]. Its standardized incidence is estimated at 36.1 per 100,000 women in West Africa [2]. In Senegal, as in most Sub-Saharan African (SSA) countries, breast cancer is the second most common cancer in women after cervical cancer, and may now be the most common cancer based on preliminary reports [2]. It is currently estimated that 5–10% of breast cancers are due to an inherited predisposition [3‐5]. Approximately 20–25% of this risk is associated to pathogenic variants of two high penetrance susceptibility genes, BRCA1 and BRCA2, located on chromosomes 17q21 and 13q12, respectively [6, 7]. Both genes are involved in DNA repair and other important biological functions [8]. Risk increases with the number of affected women within the family, early age at diagnosis and the degree of relationship with other affected women [9‐11]. The cumulative risk of breast cancer by age 80 years was estimated to 72% for BRCA1 carriers and 69% for BRCA2 carriers. For ovarian cancer the cumulative risk by age 80 years was estimated to 44% for BRCA1 carriers and 17% for BRCA2 carriers [10‐13]. The human BRCA2 gene contains 27 exons, among which exon 11 is the largest. The coding sequence (Refseq transcript mRNA: NM_000059.3) size is 11,386 bp and it encodes a protein of 3418 amino acids (Refseq protein NP_000050) [14]. Genetic variation analysis of BRCA2 has identified a large number of different pathogenic germline variants in breast cancer patients and more than a thousand different disease–causing germline pathogenic variants were listed in the Breast Cancer Information Core Database (BIC; http://​research.​nhgri.​nih.​gov/​bic/​) and in the ClinVar database (https://​www.​ncbi.​nlm.​nih.​gov/​clinvar/​). Most BRCA2 pathogenic variants have been reported in individuals of European and Asian origin while limited information is available on SSA populations [15‐19]. Herein we report a novel pathogenic variant in BRCA2 in a consanguineous family with a family history of breast cancer.

No pathogenic variants were identified in BRCA1 in the proband. A BRCA2 pathogenic variant, namely c.5219 T > G; p.(Leu1740Ter) (according to the HGVS nomenclature), was identified in the proband. This variant is located in exon 11 of the gene and is predicted to introduce a premature stop codon at position 1740 of the BRCA2 protein. The chromatogram is shown in (Fig. 2).

This pathogenic variant was also detected in three sisters and one daughter of the index case (Fig. 1). The variant was likely transmitted to the index case by her mother (III-2) even though she was not diagnosed with breast cancer, but has a sister who died of breast cancer. The index case’s mother in turn would likely have inherited this pathogenic variant from the grandmother (II-1) who’s sister died of breast cancer (II-3). Four healthy relatives of the index case had the pathogenic variant and would be at risk of developing breast cancer.

This pathogenic variant was not detected in any participant from the two control groups (healthy and sporadic breast cancer groups). This variant has not been described previously in BIC and ClinVar databases, nor in the literature. Other single nucleotide variants were identified in the index case in different BRCA2 exons (Table 1). These variants have been described in the literature and are classified as benign by the expert panel in the ClinVar database and therefore are not pathogenic.

For the other 14 index cases recruited for BRCA1/BRCA2 genetic testing, we identified a recurrent pathogenic variant of the BRCA1 gene in 6 families out of the 14. No pathogenic variant was detected for the remaining 8 families (data not shown).

Breast cancer is the most commonly diagnosed type of cancer in women in the world [2]. The epidemiology in SSA countries is characterized by younger age at diagnosis, triple negative histopathology, advanced clinical stage and poor prognosis [21‐23]. The phenotype of the breast cancer diagnosed in the studied index case matched with this epidemiology. Inherited breast cancer risk is associated to pathogenic variants of two high penetrance susceptibility genes, BRCA1 and BRCA2, yet pathogenic variants in other genes including PALB2, TP53 and PTEN have also been linked with high risk of breast cancer [24, 25]. Pathogenic variants of these genes have been associated with susceptibility to hereditary breast cancer in populations of European and Asian origin [16‐18, 26‐29] while in Africa, most of the available data come from studies conducted among North African, Nigerian, Sudan and South African populations [16, 30‐40].

Few pathogenic variants of BRCA2 gene have been reported in SSA populations. 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. The novel pathogenic variant we identified in this study is a substitution leading to premature stop codon and is located in exon 11 at position 5219.

Although other pathogenic variants surrounding this position of the BRCA2 gene have been reported in the ClinVar database, any pathogenic variant involving the particular codon has been reported in SSA populations (Table 3). These pathogenic variants lead to stop codons or frameshift at amino acid 1739, 1740 or 1741 of BRCA2 protein.

Several studies have shown that the pathogenic variant spectrum identified in black populations is different from Caucasian populations [19, 29, 47, 48]. The c.2808_2811delACAA pathogenic variant in BRCA2 was frequently reported in European populations [49], and was reported only once in a young black girl with breast cancer in Ibadan, Nigeria [27]. The pathogenic variant we identified in BRCA2 was detected in one family out of 15 recruited for BRCA1/2 genetic testing, while we identified a recurrent pathogenic variant of the BRCA1 gene in 6 families out of the 15 (data not shown). These observations confirm the diversity of pathogenic variants between populations but also within the same population [19, 37, 50].

It has also been reported that Fanconi Anemia (FA) is caused by biallelic FANCD1/BRCA2 pathogenic variants [51]. In this family it was unclear whether there was family member with Fanconi anemia like symptoms or early death, or not.

We report a novel pathogenic variant c.5219 T > G p.(Leu1740Ter) in BRCA2 in a consanguineous Senegalese family with a family history of breast cancer. This result highlights the diversity of hereditary breast cancer pathogenic variants and extends the knowledge of genetic susceptibility to breast cancer in Africa. The benefits of clinical genetic testing of BRCA1/2 in prevention and personalised treatment is unquestionable and it should be adapted to each population’s intrinsic genetic characteristics.