title: Pathogenic germline MCM9 variants are rare in Australian Lynch-like syndrome patients.
abstract: Lynch syndrome is a hereditary cancer syndrome caused by the autosomal dominant inheritance of loss-of-function mutations in DNA mismatch repair (MMR) genes. Approximately one quarter of clinically suspected cases have no identifiable germline mutation in any MMR gene, a condition known as Lynch-like syndrome (LLS). MCM9 was recently identified as the DNA helicase in the mammalian MMR complex and loss of helicase activity results in microsatellite instability. We hypothesized that pathogenic variants in MCM9 may account for LLS. The 5'UTR and coding region of MCM9 were sequenced in germline DNA of 109 Australian patients with LLS and variants were cross-referenced with three population-based databases (dbSNP144, 1000 Genomes, ExAC). The functional effect of variants was assessed in silico with PolyPhen-2, SIFT and CONDEL. Fifteen variants that included six common SNPs and nine variants of unknown significance (VUS) were identified. We conclude that VUS occur in MCM9 in a small proportion of LLS patients and MCM9 mutations are unlikely to explain most LLS cases.
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales 2052, Australia.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales 2052, Australia.
authors.forename: Luke B
authors.initials: LB
authors.lastname: Hesson
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales 2052, Australia.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Nunez
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales 2052, Australia.
authors.forename: Deborah
authors.initials: D
authors.lastname: Packham
authors.affiliation: School of Medical Sciences, UNSW Australia, Sydney, New South Wales 2052, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hawkins
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales 2052, Australia; Level 3 Brian Wilson Chancellery, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: r.ward@uq.edu.au.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales 2052, Australia. Electronic address: m.sloane@unsw.edu.au.
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Sloane
mesh_terms: D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D019295:Computational Biology; D003198:Computer Simulation; D030541:Databases, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D064110:Minichromosome Maintenance Proteins / Q000235:genetics*; D016366:Open Reading Frames; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D020121:5' Untranslated Regions; C501931:MCM9 protein, human; D064110:Minichromosome Maintenance Proteins
keywords: DNA mismatch repair; Lynch syndrome; Lynch-like syndrome; MCM9; helicase