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Review
. 2017 Feb;18(1):93-103.
doi: 10.2174/1389202917666160805153221.

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

Daniela Alosi  1 , Marie Luise Bisgaard  1 , Sophie Nowak Hemmingsen  1 , Lotte Nylandsted Krogh  2 , Hanne Birte Mikkelsen  1 , Marie Louise Mølgaard Binderup  1
Affiliations
Review

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

Daniela Alosi et al. Curr Genomics. 2017 Feb.

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.

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

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Figures

Fig. (1)
Fig. (1)
Pedigree of the presented family.
Fig. (2)
Fig. (2)
A-D: Histology and immunohistochemistry on renal tumor tissue with apparently normal cortex. A: H&E stained cortex with glomeruli (G). B: Neighbor section; strong cytoplasmic staining for pVHL in distal tubules (arrow) and weaker staining in proximal tubules; glomeruli were unstained. C: H&E stained tumor tissue with clear cell carcinoma (CC), cyst (Cy), glomerulus, and connective tissue. D: Neighbor section was without immunoreaction for pVHL. Bar: 100µm.
Fig. (3)
Fig. (3)
Overview of the evaluation of VUS pathogenicity. VUS: Variant of unknown significance, LOH: Loss of Heterozygosity, IHC: Immunohistochemistry.
See this image and copyright information in PMC

References

    1. Easton D.F., Deffenbaugh A.M., Pruss D., Frye C., Wenstrup R.J., Allen-Brady K., Tavtigian S.V., Monteiro A.N., Iversen E.S., Couch F.J., Goldgar D.E. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am. J. Hum. Genet. 2007;81(5):873–883. - PMC - PubMed
    1. Larsen M.J., Thomassen M., Gerdes A.M., Kruse T.A. Hereditary breast cancer: clinical, pathological and molecular characteristics. Breast Cancer (Auckl.) 2014;8:145–155. - PMC - PubMed
    1. Cheon J.Y., Mozersky J., Cook-Deegan R. Variants of uncertain significance in BRCA: a harbinger of ethical and policy issues to come? Genome Med. 2014;6(12):121. - PMC - PubMed
    1. Culver J.O., Brinkerhoff C.D., Clague J., Yang K., Singh K.E., Sand S.R., Weitzel J.N. Variants of uncertain significance in BRCA testing: evaluation of surgical decisions, risk perception, and cancer distress. Clin. Genet. 2013;84(5):464–472. - PMC - PubMed
    1. Maher E.R., Neumann H.P., Richard S. von Hippel-Lindau disease: A clinical and scientific review. Eur. J. Hum. Genet. 2011;19(6):617–623. - PMC - PubMed

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