Familial Lynch syndrome with early age of onset and confirmed splice site mutation in MSH2: A case report

Lynch syndrome (LS) is an autosomal dominant cancer syndrome. It can be caused by mutations of several genes, including MLH1, MSH2, MSH6, PMS2, MLH3 and MSH3, which are responsible for DNA mismatch repair, and LS affects 3-5% of patients with colorectal cancer (CRC). LS is associated with a high risk of cancer in several different locations, although the most commonly affected regions are the colon (20-70% risk), endometrium (15-70% risk), stomach (6-13% risk) and ovaries (4-12% risk). In the present report, the familial case of LS with a detected pathogenic variant in the MSH2 gene is described. The proband was a male who was diagnosed with CRC at the age of 25 years. Genealogy analysis revealed a total of seven affected relatives (including the proband), one of whom (I degree relative, mother) had synchronous cancers (endometrial and ovarian) and five others (of II and III degree relation) had ovarian cancer. Genetic analysis using next generation sequencing detected a heterozygous germline mutation in the MSH2 gene (c.1386 + 1G >A) in the proband and his mother, confirming the diagnosis of LS. The results of the recommended genetic test in an asymptomatic relative of the proband (II degree relative, uncle), found the same familial mutation. Subsequent prophylactic colonoscopy of this relative revealed early stage CRC. The presented case confirms the need for specific genetic analysis, alongside genetic counseling, in hereditary cancer syndromes. Active genetic prophylaxis in patients with LS allows early detection of primary cancers in other locations, and pre-symptomatic genetic analysis of relatives is an option for early diagnosis.