Comprehensive Mutation Analysis ofPMS2in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome

Abstract

Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands. Furthermore, we studied concordance between tumor IHC/MSI (immunohistochemistry/microsatellite instability) profile and mutation carrier state. Overall, we found 52 different pathogenic PMS2 variants explaining 121 Lynch syndrome and nine CMMRD patients. In vitro mismatch repair assays suggested pathogenicity for three missense variants. Ninety-one PMS2 mutation carriers (70%) showed isolated loss of PMS2 in their tumors, for 31 (24%) no or inconclusive IHC was available, and eight carriers (6%) showed discordant IHC (presence of PMS2 or loss of both MLH1 and PMS2). Ten cases with isolated PMS2 loss (10%; 10/97) harbored MLH1 mutations. We confirmed that recently improved mutation analysis provides a high yield of PMS2 mutations in patients with isolated loss of PMS2 expression. Application of universal tumor prescreening methods will however miss some PMS2 germline mutation carriers.

In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation

“…Moreover, it was also detected in a LS patient with a pathogenic PMS2 mutation (c.354-1G>A, p.?) (30). These three cases did not have a phenotype consistent with constitutional MMR deficiency, thus supporting their functional re-classification as neutral (Supplementary Table 2).…”

A 30-Year-Old Man with Three Primary Malignancies: A Case of Constitutional Mismatch Repair Deficiency

“…The most frequent underlying gene defects were PMS2 mutations, which were reported in approximately 60% of cases 4. The remaining 40% of cases were equally distributed among MSH6 and MLH1 / MSH2 biallelic mutation carriers 5.…”

The Perils of Single-Site Genetic Testing for Hereditary Cancer Syndromes in the Era of Next-Generation Sequencing

“…In childhood, patients with this syndrome develop brain tumors, colorectal cancers, and hematologic malignancies [2]. Additionally, functional studies of PMS2 c.319C>T found mismatch repair deficiency, resulting in less than 20% relative repair efficiency [3]. As a result of this additional information, the patient reported back to RPHCP.…”