Abstract 5613: Unclassified variants and missense polymorphisms in BRCA1 and BRCA2 genes in Algerian breast/ovarian cancer families

Abstract Background: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. Unclassified variants (UVs) and missense polymorphisms in BRCA genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our present study is to characterize UVs and missense polymorphisms in Algerian breast/ ovarian cancer patients and relatives tested previously for BRCA1/2 genes germline mutations. Methods: We analyzed 86 DNA samples from 70 breast/ovarian cancer families. The approach used is based on BRCA1/2 sequence variants screening by High-Resolution Melting (HRM) curve analysis followed by direct sequencing. To identify no synonymous amino acid changes likely to disrupt BRCA1/2 genes function, we used a comparative evolutionary bioinformatic program, Polymorphism Phenotyping 2 (PolyPhen-2). We used GeneSplicer program to identify the splice site alterations of new UVs occurring in intron-exon boundaries of BRCA1 and BRCA2 genes. Results: 76 unclassified variants and polymorphisms were detected in BRCA1/2 genes (18 BRCA1 and 58 BRCA2). 8 new missense UVs identified in the present study: two BRCA1 (c.4066C>A/p.Gln1356Lys, c.4901G>T/p.Arg1634Met) located respectively in exons 11 and 16, and six BRCA2 (c.1099G>A/p.Asp367Asn, c.2636C>A/p.Ser879Tyr, c.3868T>A/p.Cys 1290 Ser, c.5428G>T/ p.Val1810Phe, c.6346C>G/ p.His2116Asp and c.9256G>A/ p.Gly3086Arg) located respectively in exons 10, 11 and 24, show a damaging PSIC score yielded by PolyPhen-2 program and could be pathogenic. Interestingly, the new BRCA2 UV c.6346C>G/pHis2116Asp had been detected in breast/ovarian cancer patient (tested negative for a BRCA mutation) but not in her sister (diagnosed with breast cancer) who carries the BRCA1 mutation c.83_84delTG. The rare BRCA1 UV c.5332G>A/p.Asp1778Asn was found here for the first time in co-occurrence in trans with the deleterious BRCA1 mutation c.798_799delTT in young breast cancer patient. In addition, 10 new identified UVs (3 BRCA1 and 7 BRCA2) occurring in intron-exon boundaries could be considered as benign, because the GeneSplicer prediction program shows no splice alteration site for these variants. Common polymorphisms BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Lys1183Arg, Ser1613Gly and BRCA2 Asn289His, Asn372His, p.Asn991Asp have been identified with high frequency in patients who tested negative for BRCA mutations. These missense polymorphisms could have a role as susceptibility breast cancer markers in Algerian BRCAX families. Conclusions: UVs and missense polymorphisms in BRCA1/2 genes have been characterized in Algerian breast/ovarian cancer families. Evaluation of risk of breast/ovarian cancer by the eight new missense UVs and common polymorphisms identified in our present work is on going in a larger study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5613. doi:10.1158/1538-7445.AM2011-5613