A Rare MSH2 Variant as a Candidate Marker for Lynch Syndrome II Screening in Tunisia: A Case of Diffuse Gastric Carcinoma

Abstract

Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected of both HDGC and LS II syndromes. We selected the index case “JI-021”, which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G>A classified as a variant with uncertain significance (VUS) and a novel FANCD2 variant c.1879G>T. The structural prediction model of the MSH2 variant and electrostatic potential calculation showed for the first time that MSH2 c.728G>A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. It appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G>T FANCD2 variant was predicted to destabilize the protein structure. Our results showed that the MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability, and molecular modeling analysis highlights a putative impact on the binding with MLH1 by disrupting the electrostatic potential, suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in the Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with diffuse GC with suspicion of LSII and colorectal cancer allowing better clinical surveillance for more personalized medicine.

Uncovering the clinical relevance of unclassified variants in DNA repair genes: a focus on BRCA negative Tunisian cancer families

“…This in-frame deletion is located in the exon 4 of CHEK2 gene and predicted to lead to the loss of two amino acids, Among the selected variants, c.728G>A in MSH2 gene was identified in one breast cancer case with a family history of ovarian, gastric and lung cancers. Interestingly, this same variant was recently described in a Tunisian patient with gastric cancer that has a family history of breast, ovarian, and colon cancers (Kabbage et al, 2022). In this same study, structural bioinformatics analyses revealed that this variant is involved in the MSH2-MLH1 complex stability and may impact on the binding of MSH2 protein with MLH1 by disrupting the electrostatic potential which is suggestive of a pathogenic effect.…”

“…Indeed, this variant, which was described in a gastric cancer patient, appears to affect the MSH2-MLH1 complex as well as DNAcomplex stability. Interestingly, both cases carrying this variant (current report & Kabbage et al, 2022) showed family history of cancer suggestive of lynch syndrome involving breast, gastric and ovarian malignancies which in turn may support the pathogenicity of the c.728G>A variant. In addition to MMR genes, we have identified a likely pathogenic splicing variant in RAD50 gene that was predicted to lead to exon skipping (c.3036+5G>A).…”

“…Nevertheless, family history of both probands were consistent with lynch syndrome tumor spectrum which in turn may support the pathogenicity of the identified variants. Among the other MMR genes, we have identified a missense variant, c.728G>A in MSH2 gene that seems to be likely pathogenic based on the findings of Kabbage et al (2022). Indeed, this variant, which was described in a gastric cancer patient, appears to affect the MSH2-MLH1 complex as well as DNAcomplex stability.…”

“…For the missense variant identified within the MSH2 gene, no further investigations were performed, as findings of the study of Kabbage et al (2022) are suggestive of a likely pathogenic effect.…”