Profile of BRCA1/2 variants in patients from CEMIC and the University of Buenos Aires including novel findings, deleterious mutations, variants affecting protein function, and recurrent germline mutations

SOLANO A; CARDOSO F; POLETTA F; MARQUES JM; NUÑEZ L; ROMANO V; QUIROGA S; LOPEZ CAMELO JS; PODESTA E; MANDO O

Congreso; ASCO 2015; 2015

Background: Sequence data related to inherited cancers associated genes is scarce for South America population. Genetic variants of the BRCA1/2 genes, as a result of 15 years of experience in patients with diagnostic and/or family history of breast/ovarian cancer (HBOC) will be depicted. We found novel variants with clinical significance benign, uncertain (UN) and deleterious, surprisingly, even after more than 1700 causal mutations listed in the Breast Cancer Information Core (BIC), that might emphasize our hypothesis about regional variants. Methods: Massive parallel sequencing (Ion Torrent) with Sanger confirmation in DNA samples extracted from blood, analyzing the full coding sequence and 30bp of the introns of the BRCA1/2 genes, this is since two years, before that we performed Sanger sequence. Results: We analyzed 524 patients (including 144 healthy women). We detected near 400 genetic variants including 71 of them novel (30% intronics). Among the 148 mutated patients we detect three recurrent mutations: c.181T > G and c.211A > Gin BRCA1 and c.2808_2811delACAA in BRCA2. We found 24 novel mutations as follows: sixteen (7 in BRCA1 and 9 in BRCA2) are deleterious; eight variants c.4484+3A > G and p.S114C in BRCA1 and p.G173C, c.7426_7428delGAA (in frame deletion), p.D2680N, p.K426T, p.S1106G and p.A2387P in BRCA2 which resulted in either putative altered splicing (the intronic +3 variant and the base change affecting the last base of the exon c.517 C > T at the G173C), or as result of the in silico analysis probably/possibly damaging. Conclusions: a) The few recurrent mutations makes unviable the design of a panel for our population; b) The high number of novel variants reinforces the necessity for the full sequencing and the report of all the variants detected; c) This data will contribute with South American genetic variants enlarging knowledge in worldwide bases that have been (and certainly are), so generous in our development