Lynch syndrome associated with two MLH1 promoter variants and allelic imbalance of MLH1 expression

Human Mutation
Luke B HessonRobyn L Ward

Abstract

Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that...Continue Reading

References

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Dec 2, 2014·Epigenetics : Official Journal of the DNA Methylation Society·Luke B HessonRobyn L Ward

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Citations

Jun 10, 2016·Cellular Oncology (Dordrecht)·M M HahnA Geurts van Kessel
Oct 16, 2016·Trends in Molecular Medicine·Brian H ShirtsTom Walsh
Sep 12, 2015·Oncotarget·Rebecca C PoulosJason W H Wong
Jun 15, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Qing LiuJohn E Pimanda

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Methods Mentioned

BETA
PCR
electrophoresis
methylome
NOMe-Seq

Software Mentioned

GATK
Pindel
InSiGHT
Bowtie2

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