Pathogenicity Prediction for a MissenseVariant in Position p.Lue۲۶۵۳Pro of BRCA۲ Gene Involvedin Breast Cancer

Background: Breast cancer is the most common cancer of adolescents and young adult women aged ۱۵ to ۳۹ years, accountingfor ۵.۶% of all invasive breast cancer in women.Breast cancer susceptibility gene ۲ (BRCA۲) is the main geneassociated with hereditary breast cancers, which has the highestlevel of expression in the bone marrow. BRCA۲ is involvedin the maintenance of genome stability, specifically the homologousrecombination pathway for double-strand DNA. TheBRCA۲ gene was found on chromosome ۱۳q۱۲.۳ in humans.The BRCA۲ protein contains several copies of a ۷۰ aa motifcalled the BRC motif, and these motifs mediate binding to theRAD۵۱ recombinase which functions in DNA repair. BRCA۲is considered a tumor suppressor gene, as tumors with BRCA۲mutations generally exhibit loss of heterozygosity of the wildtypeallele.Materials and Methods: In BRCA۲ gene amino acid leucinereplace with proline in position ۲۶۵۳ (c.۷۹۵۸T>C:p.Leu۲۶۵۳Pro: rs۸۰۳۵۹۰۲۲). Clinvar database of reportedBRCA۲ missense variants in breast cancer was accessed andclassified as Likely-Pathogenic. By determining the location ofamino acids in this variant, using several bioinformatics predictiveprograms, the score of the algorithms was examined.Results: This mutation predicts to be probably damaging witha score of ۱.۰۰۰ by PolyPhen۲ and predicted to be a pathogenicvariant with a score of ۰.۸۹۶ by PANTHER, ۰.۸۳۹ by PhDSNP,۰.۷۵۰ by SNAP, ۰.۸۱۴ by Meta-SNP and ۰.۰۰۰ by SIFT.The pathogenicity score was ۱۳ in Varsome.Conclusion: nucleotide change in region ۷۹۵۸ which belongsto exon ۱۶ of BRCA۲ and the difference in shape and size ofthe mutant residue and the wild-type, hydrophobicity, and molecularweight of leucine and proline causes the change of thethree-dimensional shape of the encoded protein and creates anabnormal and pathogenic state.