Germline mutation in BRAF codon 600 is compatible with human development: De novo p.V600G mutation identified in a patient with CFC syndrome

K. J. Champion, C. Bunag, A. L. Estep, J. R. Jones, C. H. Bolt, R. C. Rogers, Katherine A Rauen, D. Everman

Research output: Contribution to journalArticle

13 Scopus citations


BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio-facio-cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild-type BRAF but is less strongly activating than the cancer-associated p.V600E mutation.

Original languageEnglish (US)
Pages (from-to)468-474
Number of pages7
JournalClinical Genetics
Issue number5
StatePublished - May 2011
Externally publishedYes



  • BRAF
  • Cardio-facio-cutaneous syndrome
  • Germline
  • P.V600E
  • P.V600G
  • Ras/MAPK pathway
  • RASopathy
  • Signal transduction

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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