Germline testing of Iranian families suspected of Lynch syndrome: molecular characterization and current surveillance of families with pathogenic variants in MSH2, MSH6, and PMS2

Lynch syndrome accounts for 3-5% of all colorectal and endometrial cancer cases, and suboptimal management of Lynch syndrome in the Middle East resulted in the underdiagnosis of mutation carriers. Probands from 24 unrelated Iranian families with a history of cancer(s) suggestive of Lynch syndrome underwent microsatellite instability analysis or immunohistochemistry, multigene panel testing, copy number variation detection, or multiplex ligation-dependent probe amplification. Pathogenic variants were identified in five patients (21%), including three in MSH2 , one in MSH6 , and one in PMS2. Microsatellite instability analysis showed the lengths of the CAT25 marker in tumor and normal samples were 149 and 148 bp, respectively. Among 21 family members with Lynch syndrome in the MSH2 gene, identified from the three families who previously underwent cascade screening, colorectal and endometrial cancers were the most frequent. While 66% of patients had insurance that included coverage for mutation carrier screening, only one insurance provider extended coverage for next-generation sequencing. Special attention to probands and telematic management of at-risk relatives to organize blood sample collection at their convenience enhanced cascade testing 20-fold per proband. In conclusion, the age of onset and segregation analysis indicated that PMS1 may not be a cancer susceptibility gene, and the tumor spectrum in MSH2 pathogenic carriers is similar to Western countries. Collecting blood samples at patients' convenience is a possible strategy to reduce the cost of identifying Lynch syndrome through cascade testing. The genetic analysis of patients for inherited cancers would optimize the current management of Lynch syndrome in Iran by omitting noncarriers from surveillance programs.