title: Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome.
abstract: 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.
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Champion
authors.forename: C
authors.initials: C
authors.lastname: Bunag
authors.forename: A L
authors.initials: AL
authors.lastname: Estep
authors.forename: J R
authors.initials: JR
authors.lastname: Jones
authors.forename: C H
authors.initials: CH
authors.lastname: Bolt
authors.forename: R C
authors.initials: RC
authors.lastname: Rogers
authors.forename: K A
authors.initials: KA
authors.lastname: Rauen
authors.forename: D B
authors.initials: DB
authors.lastname: Everman
mesh_terms: D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D003062:Codon / Q000235:genetics*; D004476:Ectodermal Dysplasia / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D005145:Face; D019066:Facies; D005183:Failure to Thrive / Q000235:genetics; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D003062:Codon; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases