Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Constitutional Mismatch Repair-Deficiency (CMMR-D) is a rare inherited cancer predisposition syndrome.
• It is primarily associated with germline mutations in mismatch repair (MMR) genes, leading to microsatellite instability.

Observation:

• A patient presented with CMMR-D starting at age 10, developing numerous adenomas and four malignancies over 25 years.
• The patient harbored biallelic pathogenic variants in the PMS2 gene, with absent PMS2 protein expression in tumors and normal tissues.
• Family members carried different PMS2 variants, and the proband also had variants in MSH2, APC, and CHEK2 genes.

Findings:

• Tumor tissue exhibited diffuse DNA microsatellite instability, consistent with MMR deficiency.
• Genetic analysis confirmed biallelic PMS2 germline pathogenic variants in the proband.
• The complex phenotype suggests potential contributions from other genetic alterations beyond PMS2.

Implications:

• Accurate diagnosis of CMMR-D can be challenging, necessitating comprehensive genetic evaluation.
• Further research is needed to understand how constitutional alterations in other genes contribute to the CMMR-D phenotype.
• This case highlights the importance of investigating additional genetic factors in complex hereditary cancer syndromes.