Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition

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Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of ~1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability. Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.


  • Swedish Extended Genetic Analysis of Colorectal Neoplasia (SWEN) Study Group
  • Alisa Olkinuora
  • Taina T. Nieminen
  • Emma Mårtensson
  • Anna Rohlin
  • Ari Ristimäki
  • Laura Koskenvuo
  • Anna Lepistö
  • Samuel Gebre-Medhin
  • Margareta Nordling
  • Päivi Peltomäki
Enheter & grupper
Externa organisationer
  • University of Helsinki
  • Ohio State University
  • Göteborgs universitet
  • Region Skåne
  • Sahlgrenska University Hospital
  • Helsinki University Central Hospital

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik


Sidor (från-till)1868-1873
TidskriftGenetics in Medicine
Tidigt onlinedatum2018 dec 21
StatusPublished - 2019
Peer review utfördJa