title: What you are missing could matter: a rare, complex BRAF mutation affecting codons 599, 600, and 601 uncovered by next generation sequencing.
abstract: Testing for somatic mutations in tumor samples is becoming standard practice in a number of tumor types where targeted therapies are available. Since clinical care is dependent on the identification of the presence or absence of specific mutations, it is important that these mutations be identified consistently and accurately. Here we identify in a patient with metastatic melanoma a novel, complex mutation involving BRAF c.1798A>T (p.T599T), c.1799T>A (p.V600E), and c.1803A>T (p.K601N) that was identified by next generation sequencing but not by standard testing methods. The patient was started on a combination therapy inhibiting both BRAF and MEK, and demonstrated a dramatic clinical response. This case highlights the need for improved methods of mutation testing in tumor samples and exposes a pitfall in allele-specific testing methods that can be overcome using next generation sequencing.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jennifer J D
authors.initials: JJ
authors.lastname: Morrissette
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: McGettigan
authors.affiliation: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Roth
authors.affiliation: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Elder
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.affiliation: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: Robert.Daber@uphs.upenn.edu.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Daber
mesh_terms: D003062:Codon; D004252:DNA Mutational Analysis; D005260:Female; D023281:Genomics; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D057285:Precision Medicine; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D003062:Codon; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF mutation; Personalized medicine; next generation sequencing; targeted therapies