Codon 167 missense mutations in von Hippel-Lindau syndrome: Genotype-phenotype correlations in a population-based study.

10608 Background: Von Hippel-Lindau (VHL) disease is caused by germline mutations of the VHL gene, resulting in multicentric and multiorgan tumors. Codon 167 is most commonly affected by pathogenic missense mutations (MMs). The objective of this study is to elucidate the clinical features of individuals with germline pathogenic MMs at codon 167 of VHL . Methods: 674 patients from 282 unrelated families were enrolled. Their clinical features and prognosis were reviewed. Results: 86 patients from 41 unrelated families were identified with codon 167 MMs, indicating codon 167 MMs account for the largest number of patients and families. Codon 167 MMs were associated with a significantly higher risk of pheochromocytoma (HR=7.384, 95%CI 4.496-12.126, P&lt;0.001), lower risks of central nervous system hemangioblastoma/CHB (HR=0.568, 95%CI 0.412-0.781, P=0.001) and renal cell carcinoma/RCC (HR=0.693, 95%CI 0.483-0.993, P=0.046). And codon 167 MMs correlated with better overall survival (HR=0.408, 95%CI 0.210-0.790, P=0.008) and CHB-specific survival (HR=0.201, 95%CI 0.062-0.645, P=0.007) compared with other mutations. The most dominant types of codon 167 MMs are c.499C&gt;T p.Arg167Trp (45.3%) and c.500G&gt;A p.Arg167Gln (48.8%). Multivariate Cox regression analyses discover that the mutation type was not an independent factor for VHL-associated tumors. Conclusions: In the VHL disease population, codon 167 MMs account for more than 10% of patients and unrelated families. Individuals with codon 167 MMs had unique clinical features and should be described as a separate subtype of VHL syndrome. The results of this study were important for genetic counseling and clinical decision-making. Cox regression analyses of age-related tumor risks between codon 167 MMs, oMMs and TR. Tumor Variables Univariate analysis Multivariate analysis HR 95%CI P value HR 95%CI P value Overall Sex (Male vs. Female) 0.974 0.829-1.144 0.744 0.971 0.827-1.141 0.772 Mutational type 0.510 0.505 Codon 167 MMs 0.928 0.724-1.188 0.552 0.928 0.724-1.189 0.556 oMMs 0.905 0.762-1.076 0.258 0.905 0.761-1.075 0.254 TR Reference Reference CHB Sex (Male vs. Female) 1.157 0.956-1.401 0.135 1.149 0.949-1.391 0.154 Mutational type 0.001 0.001 Codon 167 MMs 0.566 0.411-0.778 &lt;0.001 0.568 0.412-0.781 0.001 oMMs 0.772 0.631-0.946 0.013 0.774 0.632-0.947 <jats:td