MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families.
The variants c.306+5G>A and c.1865T>A (p.Leu622His) of the DNA repair gene MLH1 occur frequently in Spanish Lynch syndrome families. To understand their ancestral history and clinical effect, we performed functional assays and a penetrance analysis and studied their genetic and geographic origins. Detailed family histories were taken from 29 carrier families. Functional analysis included in silico and in vitro assays at the RNA and protein levels. Penetrance was calculated using a modified segregation analysis adjusted for ascertainment. Founder effects were evaluated by haplotype analysis. The identified MLH1 c.306+5G>A and c.1865T>A (p.Leu622His) variants are absent in control populations and segregate with the disease. Tumors from carriers of both variants show microsatellite instability and loss of expression of the MLH1 protein. The c.306+5G>A variant is a pathogenic mutation affecting mRNA processing. The c.1865T>A (p.Leu622His) variant causes defects in MLH1 expression and stability. For both mutations, the estimated penetrance is moderate (age-cumulative colorectal cancer risk by age 70 of 20.1% and 14.1% for c.306+5G>A and of 6.8% and 7.3% for c.1865T>A in men and women carriers, respectively) in the lower range of variability estimated for other pathogenic Spanish MLH1 mutations. A common haplotype was associated with each of the identified mutations, confirming their founder origin. The ages of c.306+5G>A and c.1865T>A mutations were estimated to be 53 to 122 and 12 to 22 generations, respectively. Our results confirm the pathogenicity, moderate penetrance, and founder origin of the MLH1 c.306+5G>A and c.1865T>A mutations. These findings have important implications for genetic counseling and molecular diagnosis of Lynch syndrome.
Borràs
Ester
E
Laboratori de Recerca Translacional, Institut Català d'Oncologia, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
Pineda
Marta
M
Blanco
Ignacio
I
Jewett
Ethan M
EM
Wang
Fei
F
Teulé
Alex
A
Caldés
Trinidad
T
Urioste
Miguel
M
Martínez-Bouzas
Cristina
C
Brunet
Joan
J
Balmaña
Judith
J
Torres
Asunción
A
Ramón y Cajal
Teresa
T
Sanz
Judit
J
Pérez-Cabornero
Lucía
L
Castellví-Bel
Sergi
S
Alonso
Angel
A
Lanas
Angel
A
González
Sara
S
Moreno
Víctor
V
Gruber
Stephen B
SB
Rosenberg
Noah A
NA
Mukherjee
Bhramar
B
Lázaro
Conxi
C
Capellá
Gabriel
G
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000367:Age Factors; D000368:Aged; D001483:Base Sequence; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D045325:HCT116 Cells; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D019683:Penetrance; D013030:Spain / Q000453:epidemiology; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1