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Unique MLH1 mutations in colonic adenomas in an obligate germline Lynch syndrome carrier
  1. Stefano Serra1,
  2. Jose-Mario Capo-Chichi2,
  3. Aoife J McCarthy1,
  4. Peter Sabatini2,
  5. Runjan Chetty1
  1. 1 Laboratory Medicine Program, Divisions of Anatomical Pathology, University Health Network and University of Toronto, Toronto, Ontario, Canada
  2. 2 Clinical Laboratory Genetics, University Health Network, Toronto, Ontario, Canada
  1. Correspondence to Professor Runjan Chetty, Department of Pathology, University Health Network Laboratory Medicine Program, University of Toronto, Toronto, ON M5G 2C4, Canada; runjan.chetty{at}


Background An obligate germline Lynch syndrome carrier had four colonic adenomas removed.

Materials and methods The adenomas were evaluated for grade of dysplasia, MLH1, PMS2, MSH2 and MSH6 protein expression, microsatellite instability (MSI), BRAF, methylation status and a next-generation sequencing (NGS) panel of 52 cancer genes.

Results There were four tubular or tubulovillous adenomas from the hepatic flexure, rectosigmoid and rectum; one with low-grade and high-grade dysplasia, one with high-grade dysplasia only and two with low-grade dysplasia. All four adenomas showed retention of MLH1, MHS2 and MSH6 but complete loss of PMS2 in both low-grade and high-grade dysplasia areas.

Two of the four adenomas were MSI-high, BRAF V600E wild type and were not MLH1 methylated. NGS identified an MLH1 germline variant: NM_000249.3: c.1558+1 G>A, p.(?) in all tissue (adenomas and normal), which likely explains the pathophysiology of Lynch syndrome in this patient. Other variants were also detected in MLH1 and MSH6 in all four adenomas tested; these being reported previously in somatic colorectal cancers.

Conclusion We highlight an MLH1 variant in the colonic adenomas in an obligate Lynch syndrome carrier that resulted in PMS2 protein loss in the absence of mutations of the PMS2 gene.

  • Lynch syndrome carrier
  • mismatch repair
  • MLH1 variants
  • PMS2 loss

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  • Handling editor Cheok Soon Lee.

  • Contributors All authors contributed equally to the design, concept and writing of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; internally peer reviewed.