In deep bioinformatic characterization of a novel fumarate hydratase variant FH c.199T &gt; G; (p.Tyr67Asp) in hereditary leiomyomatosis and renal cell carcinoma

Chami, Anisse Marques; Zózimo, Thalía Rodrigues de Souza; Alves, Thiago Oliveira e; Matosinho, Carolina Guimarães Ramos; Santos, Cleydson Breno Rodrigues dos; Simões, Marcela Mattos; Cabral, Walter Luiz Ribeiro; Ricardo, Bernardo Ferreira de Paula; Filho, Agnaldo Lopes da Silva; Carvalho, Maria Raquel Santos; Braga, Letícia da Conceição

doi:10.1007/s10689-023-00335-2

Cited by 1 publication

(3 citation statements)

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“…16 Two recent studies investigated missense FH variants: c.1132G>A (p.E378K) and c.199T > G; (p.-Tyr67Asp) both initially classified as VUS. 17,18 The clinical and functional assessment suggested their likely pathogenicity. 17,18 In vitro studies predicted damaging effects on protein conformation, expression, and activity, with high cell proliferation in UL cell lines compared to WT.…”

Section: Discussionmentioning

confidence: 99%

“…17,18 The clinical and functional assessment suggested their likely pathogenicity. 17,18 In vitro studies predicted damaging effects on protein conformation, expression, and activity, with high cell proliferation in UL cell lines compared to WT. 17 In another study, Popp et al sequenced 13 FH-deficient UL and identified biallelic FH variants in all, impacting fumarase oligomerization and stability.…”

Section: Discussionmentioning

confidence: 99%

“…In the FH mutation database (2008), missense variants represented 57% of all FH variants, and were reported as commonly as truncating variants in RCC cases 16 . Two recent studies investigated missense FH variants: c.1132G>A (p.E378K) and c.199T > G; (p.Tyr67Asp) both initially classified as VUS 17,18 . The clinical and functional assessment suggested their likely pathogenicity 17,18 .…”

Section: Discussionmentioning

confidence: 99%

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Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic

Ouchene,

Wilde,

Chan‐Pak‐Choon

et al. 2024

Genes Chromosomes & Cancer

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Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re‐classification of the FH c.1039T>C variant to “pathogenic” based on ACMG/AMP criteria. Further insights into pathological recognition of FH‐deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi‐disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

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