Lynch syndrome is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) system genes, such as MLH1, MSH2, MSH6, or PMS2. It is the most common hereditary colorectal cancer syndrome. Screening is regularly performed by using microsatellite instability (MSI) or immunohistochemistry for the MMR proteins in tumor samples. However, in a proportion of cases, MSI is found or MMR immunohistochemistry is impaired in the absence of a germline mutation in MMR genes, BRAF mutation, or MLH1 hypermethylation. These cases are defined as Lynch-like syndrome. Patients with Lynch-like syndrome represent a mixture of truly hereditary and sporadic cases, with a risk of colorectal cancer in first-degree relatives that is between the risk of Lynch syndrome in families and relatives of sporadic colon cancer cases. Although multiple approaches have been suggested to distinguish between hereditary and sporadic cases, a homogeneous testing protocol and consensus on the adequate classification of these patients is still lacking. For this reason, management of Lynch-like syndrome and prevention of cancer in these families is clinically challenging. This review explains the concept of Lynch-like syndrome, potential mechanisms for its development, and methods for adequately distinguishing between sporadic and hereditary cases of this entity.
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