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Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition

Journal article
Authors A. Olkinuora
T. T. Nieminen
Emma Mårtensson
Anna Rohlin
A. Ristimaki
L. Koskenvuo
A. Lepisto
S. Gebre-Medhin
Margareta Nordling
P. Peltomaki
Published in Genetics in Medicine
Volume 21
Issue 8
Pages 1868-1873
ISSN 1098-3600
Publication year 2019
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Biomedicine, Department of Pathology
Pages 1868-1873
Language en
Keywords biallelic germline variant, MLH3, polyposis, DNA mismatch repair, hereditary, cancer, mutations, hmlh3, msh3, Genetics & Heredity
Subject categories Genetics


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 similar to 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.

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