Genotype-phenotype correlations in PMS2-associated constitutional mismatch repair deficiency (PMS2-CMMRD): a systematic literature review

Catalin Vasile Munteanu^1,2Diana Luisa Lighezan^1,3*Alexandru Capcelea⁴Adela Chirita-Emandi^2,5,6Adrian Pavel Trifa^5,7,8

• ¹Universitatea de Medicina si Farmacie Victor Babes din Timisoara, Timișoara, Romania
• ²Regional Center of Medical Genetics Timiș, Louis Țurcanu Clinical Emergency Hospital for Children, 2 Iosif Nemoianu Street, Timișoara, 300011, Romania, Timisoara, Romania
• ³Multidisciplinary Research Center for Malignant Hematological Diseases, Victor Babes University of Medicine and Pharmacy, 2 Eftimie Murgu Square Street, 300041, Timișoara, Romania, Timisoara, Romania
• ⁴Department of Medical Oncology, OncoHelp Oncology Center, 59 Ciprian Porumbescu Street, Timișoara, 300239, Romania, Timișoara, Romania
• ⁵Department of Microscopic Morphology, Genetics Discipline, Victor Babeș University of Medicine and Pharmacy, 2 Eftimie Murgu Square Street, Timișoara, 300041, Romania, Timisoara, Romania
• ⁶Center for Genomic Medicine, Victor Babeș University of Medicine and Pharmacy, 2 Eftimie Murgu Square Street, Timișoara, 300041, Romania, Timisoara, Romania
• ⁷Center of Expertise on Rare Pulmonary Diseases, Victor Babeș Clinical Hospital of Infectious Diseases and Pneumophysiology, 13 Gheorghe Adam Street, Timișoara, 300310, Romania, Timisoara, Romania
• ⁸Breast Cancer Center, The Oncology Institute ”Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, Cluj-Napoca, 400015, Romania, Cluj-Napoca, Romania

Constitutional mismatch repair deficiency (CMMRD) is a rare pediatric cancer predisposition syndrome primarily characterised by central nervous system (CNS), gastrointestinal (GI) tumours and hematological malignancies, along with NF1-like cutaneous features. The PMS2-related subtype (PMS2-CMMRD) is the most common molecular form of CMMRD, exhibiting variable severity and both early and late-onset clinical presentations. Although pathogenic and likely pathogenic PMS2 heterozygous variants are relatively frequent in healthy population, CMMRD incidence is generally rare in humans and genotype-phenotype correlations are still limited. To better characterise PMS2-CMMRD group, we collected clinical cases described in literature, using three alternative methods (VarChat, VarSome and LitVar2), starting from 102 pathogenic/likely pathogenic PMS2 variants (<50 bp) reported in ClinVar by clinical and research laboratories. PMS2-CMMRD cases were split into two distinct groups based on tumour onset age: early (diagnosis under 10 years) and later-onset (diagnosis after 10 years). Significant differences in tumour distribution were observed, with CNS tumours being most prevalent in the early-onset group, while GI tumours were more common in the later-onset group. Six PMS2 variants were associated with either early or later-onset CMMRD. Future validation through larger prospective cohort studies is necessary to confirm our findings and better understand the natural history of PMS2-CMMRD to inform clinical decision-making in PMS2-Lynch syndrome (PMS2-LS).