Double heterozygosity in the BRCA1 and BRCA2 genes in Italian family.
BACKGROUND
Double heterozygosity (DH) is an extremely rare event in which both BRCA1 and BRCA2 are mutated simultaneously in a family. To date, few cases of DH have been reported, especially in Ashkenazi populations. In Italy some cases of DH have been reported. In this study, we have described an Italian family with double heterozygosity in the BRCA genes.


METHODS
The proband is a 43-year-old woman with bilateral breast cancer. She presented two pathogenic mutations in both BRCA genes, IVS8+2T>A (c.547+2T>A;p.Gln148Aspfsx51) in BRCA1, K944X (c.2830A>T;p.Lys944X) in BRCA2 and a novel variant IVS4-57A>G (c.426-57A>G) in BRCA2, not previously described. Both mutations were inherited from the paternal lineage in the proband's family. We investigated all available members of this family and we identified other two family members with DH.


CONCLUSIONS
Our observations support the hypothesis of a non-specific severe phenotype in DH carriers in terms of age of disease onset, cumulative lifetime risk and multiple primary tumours. Furthermore, our findings confirm that in order to identify all cases of DH, it is important not to limit the identification of mutations in a single gene, but extend the analysis to BRCA1 and BRCA2 and other breast cancer susceptibility genes.
Maria Teresa
MT
Vietri
Anna Maria
AM
Molinari
Gemma
G
Caliendo
Maria Laura
ML
De Paola
D'Elia
D
Giovanna
Anna Laura
AL
Gambardella
Pasquale
P
Petronella
Michele
M
Cioffi
D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype