BRCA1 novel mutation V1736D and in silico analysis of SNP Q356R in Sudanese patients with breast cancer [version 3; peer review: 1 approved, 1 approved with reservations, 1 not approved]

Background: Breast cancer (BC) remains one of the leading causes of death in women worldwide. The BRCA1 deleterious mutation has a significant role in developing BC, and the risk has been estimated to be 46-87%. Many studies emphasize the need for mining BRCA1 gene mutations that might have a role in BC pathogenesis and could affect early disease onset. This study was conducted to screen for possible pathogenic single nucleotide polymorphisms (SNPs) in BRCA1, targeting three regions: two in exon 11 and the third in exon 20. Methods: 45 blood samples were collected from patients diagnosed with BC. DNA was extracted and selected regions were amplified by PCR using three sets of primers - two within exon 11 and one within exon 20 of BRCA1. Subsets of 10 samples were selected for each primer set (30 PCR products) and sequenced. Sequences were analyzed using various bioinformatics tools. Results: Two missense mutations were found, Q356R (rs1799950) in one patient (27 years old) and a novel SNP, V1736D, in three premenopausal patients (≤45 years), which were located within exons 11 and 20, respectively. Both detected variants were heterozygous, a status found in all patients detected with such monoallelic variation. Both missense variants underwent in silico analysis. The well-known mutation, rs1799950, was predicted to alter the protein activity, conferred by a mutant residue (R-Arg), owing to the position with a bigger size and positive charge. The novel SNP, V1736D, was predicted to play a role in the pathogenesis of BC. Conclusion: Both variants require further investigation, firstly to assess their contribution to BC and secondly to determine their potential diagnostic value when assessed in a larger population.