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Hereditary non-polyposis colorectal carcinoma (HNPCC)is an autosomal dominant disorder associated withcolorectal and endometrial cancer and a range of othertumor types.Germline mutations in the DNA mismatchrepair (MMR) genes,particularly MLH1,MSH2,andMSH6,underlie this disorder.The vast majority ofthese HNPCC-associated mutations have been proven,or assumed,given the family history of cancer,to betransmitted through several generations.To the bestof our knowledge,only a single case of a de novogermline MMR gene mutation (in MSH2) has beenreported till now.Here,we report a patient with a denovo mutation in MLH1.We identified a MLH1 Q701Xtruncating mutation in the blood lymphocytes of a malewho had been diagnosed with rectal cancer at the ageof 35.His family history of cancer was negative for thefirst- and second-degree relatives.The mutation couldnot be detected in the patient’s parents and sibling andpaternity was confirmed with a set of highly polymorphicmarkers.Non-penetrance and small family size isthe common explanation of verified negative familyhistories of cancer in patients with a germline MMR genemutation.However,in addition to some cases explainedby non-paternity,de novo germline mutations shouldbe considered as a possible explanation as well.Asguidelines that stress not to restrict MMR gene mutationtesting to patients with a positive family history are morewidely introduced,more cases of de novo MMR genegermline mutations may be revealed.
Hereditary non-polyposis colorectal carcinoma (HNPCC) is an autosomal dominant disorder associated with colorectal and endometrial cancer and a range of othertumor types. Germline mutations in the DNA mismatchrepair (MMR) genes, particularly MLH1, MSH2, and MSH6, underlie this disorder. Vast majority of the HNPCC-associated mutations have been proven, or assumed, given the family history of cancer, to be transmitted through several generations. To the best of our knowledge, only a single case of a novogermline MMR gene mutation (in MSH2) has been reported to till now.Here, we report a patient with a denovo mutation in MLH1.We identified a MLH1 Q701Xtruncating mutation in the blood lymphocytes of a malewho had been diagnosed with rectal cancer at the age of 35.His family history of cancer was negative for the first-and second-degree relatives. The mutation could not be detected in the patient’s parents and sibling and paternity was confirmed with a set of highly polymorphic markers. Non-penetrance and sma ll family size is the common explanation of verified negative family histories of cancer in patients with a germline MMR gene mobilization. Despite, in addition to some cases explained by non-paternity, de novo germline mutations should be considered as a possible explanation as well. Asguidelines that stress not to restrict MMR gene mutationtesting to patients with a positive family history are more than previously introduced, more cases of de novo MMR genegermline mutations may be revealed.