Abstract
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare, autosomal dominant tumor predisposition syndrome characterized by variable development of multiple skin and uterus leiomyomas and aggressive forms of renal cell carcinoma (RCC). Mutations in fumarate hydratase (FH), one of the proteins in homologous recombination repair, precede the development of HLRCC with high penetrance. Considering the risk of early metastasis of RCC, FH has been included in mutation screening panels. The identification of a pathogenic FH variant guides the screening for tumors in the carriers. However, variants of uncertain significance (VUS) are frequent findings, limiting the clinical value of the mutation screening. Here, we describe the associated phenotype and an in-depth, multi-step Bioinformatic evaluation of the germline FH c.199T > G (p.Tyr67 > Asp) variant segregated in an HLRCC family. Evidence for FH c.199T > G; (p.Tyr67Asp) pathogenicity includes the variant segregation with the disease in three affected family members, its absence in populational databases, and the deep evolutionary conservation of the Tyr67 residue. At the protein level, this residue substitution causes the loss of molecular bonds and ionic interactions, affecting molecular dynamics and protein stability. Considering ACMG/AMP criteria, we propose the reclassification of the FH c.199T > G; (p.Tyr67Asp) variant to “likely pathogenic”. In addition, the in-depth, in silico approach used here allowed us to understand how and why FH c.199T > G; (p.Tyr67Asp) could cause HLRCC. This could help in clinical management decisions concerning the monitoring of unaffected family members having this variant.
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Acknowledgements
We thank the patient and her family for participating in this investigation. MRSC was awarded a fellowship from the Brazilian National Research Council (Conselho Nacional de Pesquisa, CNPq, grant number 312068/2015-8, 312405/2018-9). TRS and CGRM were awarded fellowships from the Brazilian Coordenação de Pessoal de Nível Superior (CAPES). TMA was awarded an undergraduate fellowship from the Pró-Reitoria de Pesquisa da Universidade Federal de Minas Gerais (PRPq/UFMG). ALSF was awarded a grant from the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) APQ-02373-17.
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AMC, MMS, WLRC, BFPR, and CS conducted the genetic counseling and cancer risk management, dermatological, surgical, pathological, and oncological evaluation, respectively. TRSZ, TMA, CGRM, LCB, ALSF, and MRSC conducted the Bioinformatic analyses, the results of which were evaluated by all authors. The manuscript was written by AMC, TRSZ, TMA, LCB, and MRSC, and reviewed by all authors.
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This project was approved by the Ethics in Research Committee of the Universidade Federal de Minas Gerais under register numbers CAAE.01758418.0.0000.5149 and CAAE.48770621.6.0000.5149.
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Chami, A., de Souza Zózimo, T.R., Alves, T.M. et al. In deep bioinformatic characterization of a novel fumarate hydratase variant FH c.199T > G; (p.Tyr67Asp) in hereditary leiomyomatosis and renal cell carcinoma. Familial Cancer 22, 481–486 (2023). https://doi.org/10.1007/s10689-023-00335-2
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DOI: https://doi.org/10.1007/s10689-023-00335-2