title: MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families.
abstract: 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.
authors.affiliation: Laboratori de Recerca Translacional, Institut Català d'Oncologia, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Borràs
authors.forename: Marta
authors.initials: M
authors.lastname: Pineda
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Jewett
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Alex
authors.initials: A
authors.lastname: Teulé
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.forename: Cristina
authors.initials: C
authors.lastname: Martínez-Bouzas
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.forename: Judith
authors.initials: J
authors.lastname: Balmaña
authors.forename: Asunción
authors.initials: A
authors.lastname: Torres
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramón y Cajal
authors.forename: Judit
authors.initials: J
authors.lastname: Sanz
authors.forename: Lucía
authors.initials: L
authors.lastname: Pérez-Cabornero
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellví-Bel
authors.forename: Angel
authors.initials: A
authors.lastname: Alonso
authors.forename: Angel
authors.initials: A
authors.lastname: Lanas
authors.forename: Sara
authors.initials: S
authors.lastname: González
authors.forename: Víctor
authors.initials: V
authors.lastname: Moreno
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Noah A
authors.initials: NA
authors.lastname: Rosenberg
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellá
mesh_terms: 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
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1