Previously undescribed causative MLH1 gene variant associated with Lynch syndrome

Background. Lynch syndrome is a hereditary cancer syndrome associated with an increased risk of colorectal and endometrial cancer, as well as other, less common tumors. Identification of pathogenic variants, associated with Lynch syndrome, via genetic testing provides an opportunity of genetic counseling not just for the patient but also for their relatives. Genetic diagnostics for hereditary cancer syndromes in all family members has the advantage of enabling preventive measures for early diagnosis and further disease progression. This is particularly important for patients with a family cancer history. Current sequencing technologies allow analysis of not only known variants, but also previously undescribed ones.

Aim: to present a clinical case of Lynch syndrome caused by a previously undescribed likely pathogenic variant of the MLH1 gene.

Methods. The results of molecular diagnostics for the genetic cause of Lynch syndrome are presented. The proband underwent wholegenome sequencing, followed by Sanger sequencing. The proband’s relatives only underwent Sanger sequencing.

Results. The clinical case described shows a likely pathogenic variant in the MLH1 gene: chr3:37017551delT (hg38), p.Val279GlyfsTer18. Sanger sequencing was used for validation. Segregation analysis was carried out.

Conclusion. Next-generation sequencing, particularly whole-genome sequencing, allows for the analysis of all candidate genes and the identification of rare variants, including those that have not been described in the literature, that are potentially associated with disease. Timely identification of causative variants informs treatment and observation of patients. It also enables the examination of first- and second-degree relatives and provides recommendations for cancer prevention and screening.

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