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

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

Volume: 18 Issue: 1

Author(s): Daniela Alosi, Marie Luise Bisgaard, Sophie Nowak Hemmingsen, Lotte Nylandsted Krogh, Hanne Birte Mikkelsen and Marie Louise Molgaard Binderup

Affiliation:

Keywords: Genetic screening, Missense mutation, Renal cell carcinoma, VHL gene, Von Hippel-Lindau disease, Variant of unknown significance.

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.

Cite this article as:

Alosi Daniela, Bisgaard Luise Marie, Hemmingsen Nowak Sophie, Krogh Nylandsted Lotte, Mikkelsen Birte Hanne and Binderup Louise Molgaard Marie, Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the VHL Mutation p.P81S (c.241C>T), Current Genomics 2017; 18 (1) . https://dx.doi.org/10.2174/1389202917666160805153221

DOI https://dx.doi.org/10.2174/1389202917666160805153221	Print ISSN 1389-2029
Publisher Name Bentham Science Publisher	Online ISSN 1875-5488