Detection of Large Rearrangements in PMS2. D. Mancini-DiNardo1, J. W. Landon1, S. Rajamani2, K. Moyes1, C. Arnell1, I. Dorweiler1, K. Bowles1, B. Leclair1, B. Roa1 1) Myriad Genetic Laboratories, Inc., Salt Lake City, UT; 2) Myriad Genetics, Inc, Salt Lake City, UT.

   Heterozygous germline mutations in PMS2 are associated with Hereditary Non-polyposis Colorectal Cancer (HNPCC or Lynch Syndrome). As one of the four primary mismatch repair genes associated with Lynch syndrome, the functional importance of PMS2 has been clear, but its total contribution to Lynch syndrome was historically considered to be quite low. More recent studies suggest that the prevalence of PMS2 mutations is comparable to MSH6, with as much as 15% of all Lynch syndrome attributable to PMS2. While inactivation of PMS2 is caused largely by sequencing mutations, a significant proportion of all PMS2 mutations have been reported to be large rearrangements (LRs). Until recently, detection of LRs in PMS2 has been hindered by the presence of numerous pseudogenes that reside on chromosome 7, the most problematic of which is PMS2CL, lying 0.7Mb centromeric to PMS2. Due to extensive gene conversion events, this transcribed pseudogene bears striking homology to the 3 end of the functional PMS2 gene, specifically in exons 9, and 11-15. By combining various methods for analyzing PMS2, our laboratory has been successful in ascribing the correct mutational status to both PMS2 and PMS2CL in a given patient sample. Here we describe the results of our comprehensive analysis of PMS2 which includes detection of LRs in regions that are complicated by the presence of the pseudogene. Our analysis of patients who have received full gene sequencing and LR analysis of MLH1, MSH2, MSH6 and PMS2, has shown that deleterious and suspected deleterious mutations in PMS2 comprise 14.3% of all mutations detected in these HNPCC-related genes (108/755). Among these PMS2 mutation-positive patients, we determined that 25% (27/108) of these mutations are LRs compared with 75% (81/108) sequencing mutations. 29.6% of the LRs detected involve exons exclusively within the pseudogene regions. Though we have detected multiple duplications, all of the deleterious and suspected deleterious LRs we have found in PMS2 thus far have been deletions. This analysis demonstrates that LRs represent a significant portion of the PMS2 mutational spectrum, particularly within the exons shared by the pseudogene, PMS2CL. As mutations within PMS2 alone are clinically actionable, it is of critical importance to distinguish between the mutational status PMS2 and the pseudogene. Our laboratory utilizes a multi-faceted process to investigate the presence of mutations within this region in both PMS2 and PMS2CL.

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