Two germline alterations in mismatch repair genes found in a HNPCC patient with poor family history.

The Bethesda guidelines may offer more useful criteria in patients' selection for germline mismatch repair gene mutation analysis than guidelines merely based on family background. An early onset double primary colorectal cancer patient with poor family history with MSI-H status was investigated for MLH1 promoter methylation, expression of the MLH1 and MSH2 gene by immunohistochemistry and mutations in the MLH1 and MSH2 genes. The index patient carried two germline alterations, the p.Val716Met in MLH1 and the c.2210+1G>C in MSH2 genes, and both tumors failed to express MLH1 and MSH2 proteins. After subsequent analysis of the whole family of the index patient, the p.Val716Met variant can be defined as a rare polymorphism with the possible contribution of pathogenicity to tumor formation and c.2210+1G>C as a true pathogenic mutation causing an out-of-frame deletion of exon 13.