title: Recurrent and founder mutations in the PMS2 gene.
abstract: Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However, some mutations are observed repeatedly across individuals not known to be related due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here, we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations and one (c.903G>T) a probable founder. One (c.1A>G) could not be evaluated for founder mutation status. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2.
authors.affiliation: Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tomsic
authors.forename: L
authors.initials: L
authors.lastname: Senter
authors.forename: S
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: M
authors.initials: M
authors.lastname: Clendenning
authors.forename: C P
authors.initials: CP
authors.lastname: Vaughn
authors.forename: M A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.forename: J
authors.initials: J
authors.lastname: Young
authors.forename: W
authors.initials: W
authors.lastname: Samowitz
authors.forename: A
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D018703:Founder Effect; D017353:Gene Deletion; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes