PTEN germline mutations in patients first tested for other hereditary cancer syndromes: Would use of risk assessment tools have reduced health care costs?

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1516 Background: PTEN Hamartoma Tumor Syndrome (PHTS) includes patients with Cowden (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) with germline PTEN mutation. Breast, colon, endometrial cancer and GI polyposis are associated, creating overlap with Hereditary Breast and Ovarian Cancer (HBOC), Lynch (LS) and adenomatous polyposis syndromes (APS). We reviewed our PHTS patient series to find how often testing criteria for these syndromes were met or testing was pursued before PTEN. Methods: Patients were prospectively recruited by relaxed International Cowden Consortium criteria or presence of known germline PTEN mutation; mutations were identified by mutation scanning or MLPA analysis and confirmed by sequencing or quantitative PCR, respectively. Families were excluded if diagnosed with CS or BRRS before 1998, family history was unavailable, or proband was <18 yrs. Pedigree, genetic testing reports, and medical records were reviewed to determine if patients met HBOC testing criteria, Amsterdam II or Bethesda 2004 criteria, or had adenomatous polyps. Risk assessment was conducted for BRCA1/2 via the BRCAPRO, Myriad II, and Penn II models; for MLH1/MSH2/MSH6 via the PREMM1,2,6 and MMRPro models; and for PTEN via the Cleveland Clinic (CC) PTEN Risk Calculator. Results: 115 PTEN mutation-positive adult probands were identified among 3,405 patients. 53 (46.1%) met testing criteria for HBOC or LS and 34 (29.6%) underwent previous testing for HBOC, LS or APS. Average risk for BRCA1/2 and MLH1/MSH2/MSH6 mutations in tested patients were 7.5-16.9% and 33.1-41.4%, respectively; whereas PTEN mutation risks were 35.9% and 79.7%. No patient tested for APS (average PTEN mutation risk 73%) had >5 adenomas. An estimated $89,700 was spent on negative analyses for HBOC, LS and APS among patients ultimately found to have germline PTEN mutations. Conclusions: PHTS should be part of the differential diagnosis for patients referred for question of HBOC, LS or APS. Pathology review is key for patients with polyposis. Using the CC PTEN risk calculator enables clinicians to understand when PTEN mutation risk is high, allowing testing to proceed in a step-wise and cost-saving manner.