Lynch syndrome is caused by germline mutations in any of the MisMatch Repair (MMR) genes. About 37% of MSH2 variants are missense variants causing single amino-acid substitutions. Whether missense variants affect the normal function of MMR proteins is crucial both to provide affected families a more accurate risk assessment and to offer predictive testing to family members. Here we report one family, fulfilling both Amsterdam I and II criteria and Bethesda guidelines, referred to our center for genetic counselling. The proband and some of her relatives have been investigated for microsatellite instability (MSI), immunohistochemical MMR protein staining, direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). Also Subcellular Localization Assay and Splice site predictions analyses were used. A germline missense variant of uncertain significance (exon 3, p.Val161Asp) was found in MSH2 gene in proband and in some relatives. The variant was associated with lack of expression of MSH2 protein (DMMR) and MSI-High status in tumour tissues. The localization assay of the MSH2 protein showed an abnormal subcellular localization pattern of the corresponding protein. Finally, splice-site prediction analysis ruled out a potential role of new splice sites as the cause behind the lack of expression of MSH2 protein and we suppose a potential correlation with other forms of post-transcriptional regulation (circular RNAs). The variant here reported shows a high correlation with phenotype and is located in an evolutionary conserved domain. The localization assay also suggest a potential pathogenic role, thus supporting further research on this matter.
Keywords: Genetic testing; Germline mutation; Lynch syndrome; Missense variant; Pathogenic mutation.