International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation.
The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156_157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement.
Peixoto
Ana
A
Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, Porto 4200-072, Portugal.
Santos
Catarina
C
Pinheiro
Manuela
M
Pinto
Pedro
P
Soares
Maria José
MJ
Rocha
Patrícia
P
Gusmão
Leonor
L
Amorim
António
A
van der Hout
Annemarie
A
Gerdes
Anne-Marie
AM
Thomassen
Mads
M
Kruse
Torben A
TA
Cruger
Dorthe
D
Sunde
Lone
L
Bignon
Yves-Jean
YJ
Uhrhammer
Nancy
N
Cornil
Lucie
L
Rouleau
Etienne
E
Lidereau
Rosette
R
Yannoukakos
Drakoulis
D
Pertesi
Maroulio
M
Narod
Steven
S
Royer
Robert
R
Costa
Maurício M
MM
Lazaro
Conxi
C
Feliubadaló
Lidia
L
Graña
Begoña
B
Blanco
Ignacio
I
de la Hoya
Miguel
M
Caldés
Trinidad
T
Maillet
Philippe
P
Benais-Pont
Gaelle
G
Pardo
Bruno
B
Laitman
Yael
Y
Friedman
Eitan
E
Velasco
Eladio A
EA
Durán
Mercedes
M
Miramar
Maria-Dolores
MD
Valle
Ana Rodriguez
AR
Calvo
María-Teresa
MT
Vega
Ana
A
Blanco
Ana
A
Diez
Orland
O
Gutiérrez-Enríquez
Sara
S
Balmaña
Judith
J
Ramon y Cajal
Teresa
T
Alonso
Carmen
C
Baiget
Montserrat
M
Foulkes
William
W
Tischkowitz
Marc
M
Kyle
Rachel
R
Sabbaghian
Nelly
N
Ashton-Prolla
Patricia
P
Ewald
Ingrid P
IP
Rajkumar
Thangarajan
T
Mota-Vieira
Luisa
L
Giannini
Giuseppe
G
Gulino
Alberto
A
Achatz
Maria I
MI
Carraro
Dirce M
DM
de Paillerets
Brigitte Bressac
BB
Remenieras
Audrey
A
Benson
Cindy
C
Casadei
Silvia
S
King
Mary-Claire
MC
Teugels
Erik
E
Teixeira
Manuel R
MR
D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005828:Genetics, Population; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011174:Portugal / Q000453:epidemiology; D012333:RNA, Messenger / Q000032:analysis; D016364:Reading Frames / Q000235:genetics; D017384:Sequence Deletion
D012333:RNA, Messenger