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Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition.


ABSTRACT: 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.

SUBMITTER: Olkinuora A 

PROVIDER: S-EPMC6752675 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition.

Olkinuora Alisa A   Nieminen Taina T TT   Mårtensson Emma E   Rohlin Anna A   Ristimäki Ari A   Koskenvuo Laura L   Lepistö Anna A   Gebre-Medhin Samuel S   Nordling Margareta M   Peltomäki Päivi P  

Genetics in medicine : official journal of the American College of Medical Genetics 20181221 8


<h4>Purpose</h4>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.<h4>Methods</h4>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 refer  ...[more]

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