Somatic mosaicism by a de novo MLH1 mutation as a cause of Lynch syndrome

Willemina Geurts‐Giele1, Efraim Rosenberg2, Anja van Rens3, Monique van Leerdam4, Winand Dinjens1, Fonnet Bleeker3

1Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands. 2Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands. 3Familial Cancer Clinic, Netherlands Cancer Institute, Amsterdam, Netherlands. 4Department of Gastroenterology, Netherlands Cancer Institute, Amsterdam, Netherlands


Objectives/Background: Lynch syndrome (LS) is caused by germline mismatch repair (MMR) gene mutations. De novo MMR gene mutations are rare, and somatic mosaicism in LS is thought to be infrequent. We describe the first case of somatic mosaicism by a de novo MLH1 mutation for a patient diagnosed with a rectosigmoid adenocarcinoma at age 31.

Methods: Twelve years after initial colorectal cancer diagnosis, tumor tissue of the patient was tested with sensitive next generation sequencing (NGS) analysis for the presence of somatic MMR mutations.

Results: In tumor tissue, an inactivating MLH1 mutation (c.518_519del; p.(Tyr173Trpfs*18)) was detected, which was also present at low level in the blood of the patient. In both parents, as well as the patient’s sisters, the mutation was not present.

Conclusions: We show that low‐level mosaicism can be detected by using high‐coverage targeted NGS panels on constitutional and/or tumor DNA. This report illustrates that by using sensitive sequencing techniques, more cases of genetic diseases driven by mosaic mutations may be identified, with important clinical consequences for patients and family members.

Abstract references

Geurts‐Giele WR, Rosenberg EH, Rens AV, Leerdam MEV, Dinjens WN, Bleeker FE. Somatic mosaicism by a de novo MLH1 mutation as a cause of Lynch syndrome. Mol Genet Genomic Med. 2019;e699