Molecular and clinical characterization of an in frame deletion of uncertain clinical significance in the BRCA2 gene.
In this study, we analyzed a "variant of uncertain significance" (VUS) located in exon 23 of the BRCA2 gene exhibited by six members of five distinct families with hereditary breast cancer (BC). The variant was identified by DNA sequencing, and cDNA analysis revealed its co-expression with wild-type mRNA. We analyzed co-occurrence with other pathological mutations in BRCA1/2, performed a case-control study, looked for evolutionary data and used in-silico analyses to predict its potential clinical significance. Sequencing revealed an in frame deletion of 126 nucleotides in exon 23, leading to a deletion of 42 amino acids (c.9203_9328del126, p.Pro2992_Thr3033del). All of the VUS-carriers suffered from either BC or ovarian/pancreatic cancer. No other definite pathologic mutation of BRCA genes was found in the five families. The identified deletion could not be observed in a control cohort of 2,652 healthy individuals, but in 5 out of 916 (0.5%) tested BC families without a bona fide pathogenic BRCA1/2 mutation (P = 0.0011). According to these results, the in frame deletion c.9203_9328del126 is a rare mutation strongly associated with familial BC. In summary, our investigations indicate that this BRCA2 deletion is pathogenic.
Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany.
Michelle G
MG
Rath
Farnoosh
F
Fathali-Zadeh
Anne
A
Langheinz
Sandrine
S
Tchatchou
Theda
T
Voigtländer
Jörg
J
Heil
Michael
M
Golatta
Sarah
S
Schott
Teresa
T
Drasseck
Anne
A
Behnecke
Anna-Lena
AL
Burgemeister
Christina
C
Evers
Peter
P
Bugert
Hans
H
Junkermann
Andreas
A
Schneeweiss
Claus R
CR
Bartram
Christof
C
Sohn
Christian
C
Sutter
Barbara
B
Burwinkel
D000595:Amino Acid Sequence; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D019295:Computational Biology / Q000379:methods; D005091:Exons; D005190:Family; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D059645:Mutation Rate; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D017384:Sequence Deletion