Genotype-phenotype correlations in PMS2-associated constitutional mismatch repair deficiency: a systematic literature...

Constitutional mismatch repair deficiency (CMMRD) is a rare pediatric cancer predisposition syndrome primarily characterised by central nervous system (CNS), gastro-intestinal (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).