Identification of a novel PMS2 alteration c.505C>G (R169G) in trans with a PMS2 pathogenic mutation in a patient with constitutional mismatch repair deficiency

Abstract

Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare autosomal recessive predisposition to colorectal polyposis and other malignancies, often childhood-onset, that is caused by biallelic inheritance of mutations in the same mismatch repair gene. Here, we describe a patient with a clinical diagnosis of CMMRD based on colorectal polyposis and young-onset endometrial cancer who was identified to have two alterations in trans in PMS2: one known pathogenic mutation (c.1831insA; p.Ile611Asnfs*2) and one novel variant of uncertain significance (c.505C>G; p.Arg169Glu), a missense alteration. We describe the clinical and molecular features in the patient harboring this novel alteration c.505C>G, who meets clinical criteria for CMMRD and exhibits molecular evidence supporting a diagnosis of CMMRD. Although experimental validation is needed to confirm its pathogenicity, PMS2 c.505C>G likely has functional consequences that contributes to our patient's phenotype based on the patient's clinical presentation, tumor studies, and bioinformatics analysis.

Keywords: Constitutional mismatch repair deficiency; Lynch syndrome; Variant of uncertain significance.

Fig. 1

a Pedigree demonstrating family history of cancer and segregation of the PMS2 alterations b Sequencing chromatograms of germline mutations detected using LR-PCR and internal PCRs of exons 5 and 11, as well as schematic illustration of the PMS2 protein showing the known functional domains and locations of the germline mutations detected

Fig. 2

a Immunohistochemical staining of tubulovillous adenoma demonstrating intact expression of all MMR proteins, including PMS2 b Microsatellite instability analysis by PCR demonstrating high microsatellite instability in tubulovillous adenoma c Germline microsatellite instability analysis by PCR demonstrates the presence of a peak larger than the principal allele in the genomic DNA of our patient with CMMRD. Only one dinucleotide marker is shown for illustrative purposes