Constitutional MLH1 promotor hypermethylation: Clinical characteristics and testing frequency of a poorly recognized mechanism for Lynch-associated malignancies.

10581 Background: MSI-H colorectal cancer is most often a result of deleterious mutations in mismatch repair genes, but can also occur through repressed gene transcription due to hypermethylation of the MLH1 promoter, often associated with BRAF V600E mutations. However, there is a subset of patients who have a “constitutional epimutation”, resulting in hypermethylation of MLH1 throughout normal tissue. We observed a young patient develop a second primary Lynch associated malignancy (see Table 1) who was found to have a constitutional epimutation in MLH1 that prompted us to review the frequency with which the test was ordered and the positivity rate, as well as outline the clinical history in the positive cases. Methods: We reviewed all of the testing ordered for MLH1 hypermethylation of peripheral blood (MLHPB) at the Mayo Clinic Laboratory between 09/01/2020 and 09/01/2021. To the best of our knowledge, this is the only clinically available testing lab in the United States. We reviewed positive casesfor characteristics including the number of malignancies, age of diagnosis, and family history. Results: 33 MLHPB total tests were ordered in the United States at the Mayo Clinic laboratories between 09/01/2020 and 09/01/2021. Three of the tests were positive, including the single test ordered by our institution, and one of the two additional positive tests was available for detailed review. Our institution’s positive test case was a 41 year old women who developed T4N2M0 colorectal cancer 5 years after being treated for endometrial cancer. She had endometrial cancer with absence of MLH1 and PMS2 staining and had a negative germline cancer risk panel at age 36. Five years later, she developed a T4N2 colorectal cancer after which repeat germline testing with RNA sequencing was negative and she was found to have constitutional MLH1 promoter hypermethylation. We were able to obtain clinical information about two of the three individuals with positive tests (See Table). Conclusions: Recognition of constitutional MLH1 hypermethylation may allow for earlier recognition of Lynch related malignancies in affected patients and families. Testing appears infrequent and this condition often goes unrecognized. Specific consensus guidelines may improve recognition and cancer screening in this population. [Table: see text]