Clinical characteristics of patients with PMS2 mutations

Document Type

Conference Proceeding

Publication Date


Publication Title

Journal of Clinical Oncology


Background: Lynch syndrome is a hereditary cancer predisposition syndrome caused by mutations in mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. The cancer risks and clinical presentation of PMS2 associated Lynch syndrome is not well defined. This study outlines the characteristics of patients with PMS2 mutations identified in a large academic center. Methods: Patients with a pathogenic or likely pathogenic PMS2 variant identified between June 1, 2009 and Dec 31, 2021 were selected from a database at the Nancy and James Grosfeld Cancer Genetics Center at Beaumont Health. Data on demographics, cancer type and molecular testing were retrospectively analyzed. Results: A total of 92 patients from 61 families were found to carry a pathogenic or likely pathogenic variant in PMS2. The mean age at testing was 54 (19 to 95). A majority (50) of the family were Caucasian, while the rest were African American (2), Middle Eastern (2), Multiracial (8). The most common variant was c.137G > T (p.Ser46Ile), seen in twelve of 61 families. Forty-two patients (45.6%) had a personal history of cancer, with a mean age at diagnosis of 63. Of these forty-two patients, four had multiple malignancies, including one patient with six separate cancers. The most common malignancies were breast (16), colon (12), followed by uterine cancer (8), pancreatic (4), prostate (3) and other cancers. The mean age of diagnosis of breast cancer was 56 (41 to 78), colon cancers was 57 (32 to 75), uterine cancer 59 (50 to 72). Tumor IHC was performed in thirteen cases and 11 demonstrated loss of PMS2 protein expression. MSI was performed in 8 cases and 5 were unstable and 3 were stable. Conclusions: This study reveals the the clinical spectrum of cancers in PMS2 related Lynch syndrome. The most common cancers were breast, colon and uterine cancer, with older age of diagnosis. There was evidence of a more severe phenotype, exemplified by a patient with six cancers, suggesting higher penetrance. Further research is needed to better characterize the clinical presentation of PMS2 related Lynch syndrome.




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