P114: Over-representation of PMS2CL pseudogene interference in PMS2 testing in a non-European cohort

fragment sizes.Thus, we determined that the observed disruption in nucleosome positioning is more likely to be an alteration in the chromatin profiles.cfDNA nucleosomal signatures were also able to differentiate between high-and low-severity participants (p = 0.001), as well as between the high-and moderateseverity participants (p = 0.007).It did not separate moderate-from low-severity participants (p = 0.986).Nucleosome positioning in cancer-negative participants was also dysregulated compared to healthy controls (p = 0.0002), suggesting underlying disease processes without full progression to cancer.To leverage nucleosome positioning inferred using cfDNA to identify early MPNSTs, we mapped cfDNA coverage to a reference for open chromatin regions known from ATAC-seq data from MPNST that exceeded 95% peak saturation.NF1 patients demonstrated less pronounced nucleosome protection of DNA compared to healthy non-NF1 participants, particularly those with an active MPNST at the time of blood collection (p < 0.0001).This indicates disruptions in nucleosome placement that could reflect changes in chromatin structure associated with MPNST progression.Conclusion: We were able to demonstrate that NF1 leads to a global difference in cfDNA fragmentation, and that nucleosome-dependent signatures have clinical utility as a diagnostic tool.cfDNA fragment profiles correlated with severity assessments and may fill an important gap in linking between harboring an NF1 variant and projected outcomes for each patient.Further work is needed to refine cfDNA-based severity scores and establish optimal thresholds to identify high-severity NF1 patients at risk of developing an MPNST as well as early MPNSTS.This approach may also serve to tailor the frequency of cfDNA surveillance and may have broader applications in the management of hereditary cancer syndromes.