Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the VHL Mutation p.P81S (c.241C>T)

Abstract

Background: Evaluation of the pathogenicity of a gene variant of unknown significance (VUS) is crucial for molecular diagnosis and genetic counseling, but can be challenging. This is especially so in phenotypically variable diseases, such as von Hippel-Lindau disease (vHL). vHL is caused by germline mutations in the VHL gene, which predispose to the development of multiple tumors such as central nervous system hemangioblastomas and renal cell carcinoma (RCC).Objective: We propose a method for the evaluation of VUS pathogenicity through our experience with the VHL missense mutation c.241C>T (p.P81S).Method: 1) Clinical evaluation of known variant carriers: We evaluated a family of five VHL p.P81S carriers, as well as the clinical characteristics of all the p.P81S carriers reported in the literature; 2) Evaluation of tumor tissue via genetic analysis, histology, and immunohistochemistry (IHC); 3) Assessment of the variant’s impact on protein structure and function, using multiple databases, in silico algorithms, and reports of functional studies.Results: Only one family member had clinical signs of vHL with early-onset RCC. IHC analysis showed no VHL protein expressed in the tumor, consistent with biallelic VHL inactivation. The majority of in silico algorithms reported p.P81S as possibly pathogenic in relation to vHL or RCC, but there were discrepancies. Functional studies suggest that p.P81S impairs the VHL protein’s function.Conclusion: The VHL p.P81S mutation is most likely a low-penetrant pathogenic variant predisposing to RCC development. We suggest the above-mentioned method for VUS evaluation with use of different methods, especially a variety of in silico methods and tumor tissue analysis.

Hereditary Endocrine Tumor Registries

“…Overall, 136 peer-reviewed publications based on registry data were identified. Of these, basic science was most commonly represented (80 papers [ 15‐94 ]) followed by clinical outcome (30 papers [ 95‐124 ]), quality and improvement (7 papers [ 125‐131 ]), treatment (6 papers [ 132‐137 ]), epidemiology (4 papers [ 98 , 138‐140 ]), patient-reported outcome (PRO) measure (1 paper [ 141 ]), and other (3 papers [ 142‐144 ]). Additionally, there were 5 registry-issued clinical practice guidelines [ 145‐149 ] published in collaboration with other institutions and specialty societies.…”

Zebrafish Is a Powerful Tool for Precision Medicine Approaches to Neurological Disorders

“…This is particularly relevant in the case when Variants of Unknown Significance (VUS) are identified in patients. These genetic variations for which we do not know the molecular and physiological consequences represent a significant dilemma in genetic diagnosis and genetic counseling ( Alosi et al, 2017 ). Indeed, according to the American College of Medical Genetics and Genomics (ACMG) guidelines, VUS should not be used in clinical decision-making ( Richards et al, 2015 ).…”

Mutation of the proline P81 into a serine modifies the tumour suppressor function of the von Hippel–Lindau gene in the ccRCC

“…Among the 1230 mutations listed in the VHL database (http://umd.be/VHL) some mutants still remain biochemically uncharacterized [3]. Referred families diagnosed with P81S mutation linked to low penetrance Type 1 von Hippel-Lindau disease and a mild phenotype [9] [10]. A previous study investigating defects Type 2C associated mutant protein demonstrated at the molecular level the deleterious role involvement of pVHL L188V , pVHL P81S/L188V , pVHL V84L.…”