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Gene(s) annotations

Available GET parameters:

add-all-data = 1 or 0 
add-region-databases = 1 or 0 
expand-pubmed-articles = 1 or 0 
add-main-data-points = 1 or 0 
add-varsome-user-entries = 1 or 0 
add-source-databases = all or none or dbnsfp-genes,civic,ghr-genes,dgi,genomics-england-panelapp,weill-cornell-medicine-pmkb,unil-domino,aact,cgd,exac-genes 
allele-frequency-threshold = float 
add-ACMG-annotation = 1 or 0 
minimum-clinvar-stars = 0 or 1 or 2 or 3 or 4 
exclude-source-databases = dbnsfp-genes,civic,ghr-genes,dgi,genomics-england-panelapp,weill-cornell-medicine-pmkb,unil-domino,aact,cgd,exac-genes 
use-canonical-transcript = 1 or 0 
override-transcript = str
GET /lookup/gene/BRAF/hg19?add-all-data=1
HTTP 200 OK
Allow: GET, POST, HEAD, OPTIONS
Cache-Control: max-age=300
Content-Type: application/json
ETag: "8e24280a24ff9d16e7c1c67715c4801b"
Vary: Accept

{
    "symbol": "BRAF",
    "gene_id": 2273,
    "description": "B-Raf proto-oncogene, serine/threonine kinase",
    "synonyms": [
        "BRAF1"
    ],
    "dgi": {
        "version": "22_sep_2019",
        "items": [
            {
                "drug_name_primary": "Plx-4720",
                "drug_chembl_id": "CHEMBL1230020",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Advanced Solid Tumor"
                    },
                    {
                        "name": "Colon Cancer",
                        "id": 30010000001635
                    },
                    {
                        "name": "Colorectal Cancer",
                        "id": 30010000004812
                    },
                    {
                        "name": "Glioblastoma Multiforme",
                        "id": 30010000017081
                    },
                    {
                        "name": "Malignant Glioma",
                        "id": 30010000014887
                    },
                    {
                        "name": "Melanoma",
                        "id": 30010000004393
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": [
                    "inhibitor"
                ],
                "drug_fda_approved": false,
                "attributes": [
                    {
                        "drug_family": "BRAF inhibitor"
                    },
                    {
                        "alteration": "BRAF:V600E"
                    },
                    {
                        "specific_action_of_the_ligand": "Inhibition"
                    },
                    {
                        "endogenous_drug": "False"
                    },
                    {
                        "direct_interaction": "True"
                    },
                    {
                        "direct_interaction": "False"
                    },
                    {
                        "response_type": "resistant"
                    },
                    {
                        "approval_status": "Preclinical - Cell line xenograft"
                    },
                    {
                        "evidence_type": "Actionable"
                    },
                    {
                        "approval_status": "Preclinical"
                    },
                    {
                        "response_type": "predicted – resistant"
                    },
                    {
                        "response_type": "decreased response"
                    },
                    {
                        "combination_therapy": "PLX4720 + Tivozanib"
                    },
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "combination_therapy": "PLX4720 + Doxorubicin"
                    },
                    {
                        "combination_therapy": "Cediranib + Selumetinib + PLX4720"
                    },
                    {
                        "combination_therapy": "Cediranib + PLX4720"
                    },
                    {
                        "combination_therapy": "PLX4720 + Navitoclax"
                    },
                    {
                        "combination_therapy": "Erlotinib + PLX4720"
                    },
                    {
                        "combination_therapy": "PLX4720 + TAK-632"
                    },
                    {
                        "combination_therapy": "Imatinib + PLX4720"
                    },
                    {
                        "combination_therapy": "Gefitinib + PLX4720"
                    },
                    {
                        "combination_therapy": "Everolimus + PLX4720"
                    },
                    {
                        "response_type": "predicted – sensitive"
                    },
                    {
                        "approval_status": "Preclinical - Cell culture"
                    },
                    {
                        "combination_therapy": "Alpelisib + PLX4720"
                    },
                    {
                        "combination_therapy": "BI2536 + PLX4720"
                    },
                    {
                        "combination_therapy": "Selumetinib + PLX4720"
                    },
                    {
                        "combination_therapy": "PLX4720 + Vorinostat"
                    },
                    {
                        "combination_therapy": "Cetuximab + PLX4720"
                    },
                    {
                        "combination_therapy": "GDC-0941 + PLX4720"
                    }
                ]
            },
            {
                "drug_name_primary": "Cep-32496",
                "drug_chembl_id": "CHEMBL2029988",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Colon Carcinoma",
                        "id": 30010000001635
                    },
                    {
                        "name": "Melanoma",
                        "id": 30010000004393
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": [
                    "inhibitor"
                ],
                "drug_fda_approved": false,
                "attributes": [
                    {
                        "details_of_the_assay_for_interaction": "Inhibition of wild type BRAF activity."
                    },
                    {
                        "specific_action_of_the_ligand": "Inhibition"
                    },
                    {
                        "endogenous_drug": "False"
                    },
                    {
                        "direct_interaction": "False"
                    },
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "approval_status": "Preclinical - Cell line xenograft"
                    },
                    {
                        "evidence_type": "Actionable"
                    },
                    {
                        "mechanism_of_interaction": "Serine/threonine-protein kinase B-raf inhibitor"
                    },
                    {
                        "direct_interaction": "yes"
                    }
                ]
            },
            {
                "drug_name_primary": "Trametinib",
                "drug_chembl_id": "CHEMBL2103875",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Advanced Solid Tumor"
                    },
                    {
                        "name": "Collecting Duct Carcinoma",
                        "id": 30010000004500
                    },
                    {
                        "name": "Colon Cancer",
                        "id": 30010000001635
                    },
                    {
                        "name": "Colorectal Cancer",
                        "id": 30010000004812
                    },
                    {
                        "name": "Lung Adenocarcinoma",
                        "id": 30010000004352
                    },
                    {
                        "name": "Lung Cancer",
                        "id": 30010000007947
                    },
                    {
                        "name": "Melanoma",
                        "id": 30010000004393
                    },
                    {
                        "name": "Multiple Myeloma",
                        "id": 30010000008731
                    },
                    {
                        "name": "Neuroendocrine Tumor",
                        "id": 30010000018326
                    },
                    {
                        "name": "Non-Small Cell Lung Carcinoma",
                        "id": 30010000004509
                    },
                    {
                        "name": "Ovarian Cancer",
                        "id": 30010000007226
                    },
                    {
                        "name": "Pancreatic Adenocarcinoma",
                        "id": 30010000005240
                    },
                    {
                        "name": "Pancreatic Cancer",
                        "id": 30010000004475
                    },
                    {
                        "name": "Pilocytic Astrocytoma",
                        "id": 30010000015638
                    },
                    {
                        "name": "Thyroid Cancer",
                        "id": 30010000001705
                    },
                    {
                        "name": "Thyroid Carcinoma",
                        "id": 30010000014077
                    },
                    {
                        "name": "Triple-Receptor Negative Breast Cancer",
                        "id": 30010000004736
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": null,
                "drug_fda_approved": true,
                "attributes": [
                    {
                        "combination_therapy": "Dabrafenib;Trametinib"
                    },
                    {
                        "drug_family": "BRAF inhibitor;MEK inhibitor"
                    },
                    {
                        "alteration": "BRAF:V600E"
                    },
                    {
                        "combination_therapy": "Panitumumab;Dabrafenib;Trametinib"
                    },
                    {
                        "drug_family": "EGFR mAb inhibitor;BRAF inhibitor;MEK inhibitor"
                    },
                    {
                        "alteration": "BRAF:V600E,V600K"
                    },
                    {
                        "drug_family": "MEK inhibitor"
                    },
                    {
                        "drug_family": "[MEK inhibitor]"
                    },
                    {
                        "alteration": "BRAF:K601R,L597R,V600R"
                    },
                    {
                        "alteration": "BRAF__."
                    },
                    {
                        "combination_therapy": "Trametinib + Dabrafenib"
                    },
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "approval_status": "Preclinical - Cell culture"
                    },
                    {
                        "evidence_type": "Actionable"
                    },
                    {
                        "approval_status": "Preclinical"
                    },
                    {
                        "combination_therapy": "Palbociclib + Trametinib"
                    },
                    {
                        "response_type": "decreased response"
                    },
                    {
                        "approval_status": "Phase I"
                    },
                    {
                        "combination_therapy": "Dabrafenib + Everolimus + Trametinib"
                    },
                    {
                        "approval_status": "Clinical Study"
                    },
                    {
                        "response_type": "resistant"
                    },
                    {
                        "combination_therapy": "Cetuximab + Dabrafenib + Trametinib"
                    },
                    {
                        "combination_therapy": "Trametinib + TW-37"
                    },
                    {
                        "combination_therapy": "Trametinib + Navitoclax"
                    },
                    {
                        "combination_therapy": "PAC-1 + Trametinib + Vemurafenib"
                    },
                    {
                        "approval_status": "Phase II"
                    },
                    {
                        "approval_status": "Guideline"
                    },
                    {
                        "combination_therapy": "Dasatinib + Trametinib"
                    },
                    {
                        "combination_therapy": "Trametinib + Vemurafenib"
                    },
                    {
                        "approval_status": "FDA approved"
                    },
                    {
                        "combination_therapy": "BI 882370 + Trametinib"
                    },
                    {
                        "response_type": "predicted – sensitive"
                    },
                    {
                        "combination_therapy": "GSK2126458 + Trametinib"
                    },
                    {
                        "combination_therapy": "ARQ092 + Trametinib"
                    },
                    {
                        "approval_status": "Preclinical - Pdx"
                    },
                    {
                        "response_type": "no benefit"
                    },
                    {
                        "approval_status": "Phase III"
                    },
                    {
                        "combination_therapy": "INC280 + Trametinib"
                    },
                    {
                        "combination_therapy": "S63845 + Trametinib"
                    },
                    {
                        "combination_therapy": "Panitumumab + Trametinib + Dabrafenib"
                    },
                    {
                        "approval_status": "Phase Ib/II"
                    },
                    {
                        "combination_therapy": "MK2206 + Trametinib"
                    },
                    {
                        "combination_therapy": "AMG 232 + Trametinib + Dabrafenib"
                    },
                    {
                        "combination_therapy": "BKM120 + Trametinib"
                    },
                    {
                        "combination_therapy": "Dabrafenib + Trametinib"
                    },
                    {
                        "clinical_status": "FDA-approved"
                    },
                    {
                        "pathway": "activation"
                    },
                    {
                        "variant_effect": "gain-of-function"
                    },
                    {
                        "clinical_status": "case report"
                    }
                ]
            },
            {
                "drug_name_primary": "Pembrolizumab",
                "drug_chembl_id": "CHEMBL3137343",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Melanoma",
                        "id": 30010000004393
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": null,
                "drug_fda_approved": true,
                "attributes": [
                    {
                        "response_type": "no benefit"
                    },
                    {
                        "approval_status": "Preclinical"
                    },
                    {
                        "evidence_type": "Actionable"
                    },
                    {
                        "combination_therapy": "GSK2636771 + Pembrolizumab"
                    },
                    {
                        "response_type": "sensitive"
                    }
                ]
            },
            {
                "drug_name_primary": "Irinotecan",
                "drug_chembl_id": "CHEMBL481",
                "drug_immunotherapy": true,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Colorectal Cancer",
                        "id": 30010000004812
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": null,
                "drug_fda_approved": true,
                "attributes": [
                    {
                        "combination_therapy": "Cetuximab + Irinotecan"
                    },
                    {
                        "response_type": "resistant"
                    },
                    {
                        "approval_status": "Clinical Study"
                    },
                    {
                        "evidence_type": "Actionable"
                    },
                    {
                        "combination_therapy": "Irinotecan + Panitumumab"
                    },
                    {
                        "response_type": "predicted – sensitive"
                    },
                    {
                        "combination_therapy": "Vemurafenib + Cetuximab + Irinotecan"
                    },
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "approval_status": "Phase Ib/II"
                    }
                ]
            },
            {
                "drug_name_primary": "Phenmetrazine",
                "drug_chembl_id": "CHEMBL1201208",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Melanoma",
                        "id": 30010000004393
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": null,
                "drug_fda_approved": true,
                "attributes": [
                    {
                        "response_type": "no benefit"
                    },
                    {
                        "approval_status": "Preclinical"
                    },
                    {
                        "evidence_type": "Actionable"
                    }
                ]
            },
            {
                "drug_name_primary": "Panobinostat",
                "drug_chembl_id": "CHEMBL483254",
                "drug_immunotherapy": true,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Colorectal Cancer",
                        "id": 30010000004812
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": null,
                "drug_fda_approved": true,
                "attributes": [
                    {
                        "combination_therapy": "Lapatinib + Panobinostat"
                    },
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "approval_status": "Preclinical"
                    },
                    {
                        "evidence_type": "Actionable"
                    }
                ]
            },
            {
                "drug_name_primary": "Vemurafenib",
                "drug_chembl_id": "CHEMBL1229517",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Advanced Solid Tumor"
                    },
                    {
                        "name": "Cholangiocarcinoma",
                        "id": 30010000017941
                    },
                    {
                        "name": "Colon Cancer",
                        "id": 30010000001635
                    },
                    {
                        "name": "Colorectal Cancer",
                        "id": 30010000004812
                    },
                    {
                        "name": "Hairy Cell Leukemia",
                        "id": 30010000017802
                    },
                    {
                        "name": "Lung Adenocarcinoma",
                        "id": 30010000004352
                    },
                    {
                        "name": "Melanoma",
                        "id": 30010000004393
                    },
                    {
                        "name": "Neuroendocrine Tumor",
                        "id": 30010000018326
                    },
                    {
                        "name": "Non-Small Cell Lung Carcinoma",
                        "id": 30010000004509
                    },
                    {
                        "name": "Ovarian Cancer",
                        "id": 30010000007226
                    },
                    {
                        "name": "Pancreatic Cancer",
                        "id": 30010000004475
                    },
                    {
                        "name": "Renal Cell Carcinoma",
                        "id": 30010000004375
                    },
                    {
                        "name": "Thyroid Cancer",
                        "id": 30010000001705
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": [
                    "inhibitor"
                ],
                "drug_fda_approved": true,
                "attributes": [
                    {
                        "trial_name": "PLX4032, RG7204"
                    },
                    {
                        "novel_drug_target": "Established target"
                    },
                    {
                        "drug_family": "BRAF inhibitor"
                    },
                    {
                        "alteration": "BRAF:V600D,V600K,V600M,V600G,V600R"
                    },
                    {
                        "alteration": "BRAF:V600E"
                    },
                    {
                        "combination_therapy": "Vemurafenib;Cobimetinib"
                    },
                    {
                        "drug_family": "BRAF inhibitor;MEK inhibitor"
                    },
                    {
                        "alteration": "BRAF:V600E,V600K"
                    },
                    {
                        "alteration": "BRAF:V600."
                    },
                    {
                        "alteration": "BRAF:V600E,V600D,V600K,V600M,V600G,V600R"
                    },
                    {
                        "combination_therapy": "Vemurafenib;Panitumumab"
                    },
                    {
                        "drug_family": "BRAF inhibitor;EGFR mAb inhibitor"
                    },
                    {
                        "alteration": "MET:amp;BRAF:V600E"
                    },
                    {
                        "combination_therapy": "Crizotinib;Vemurafenib"
                    },
                    {
                        "drug_family": "ALK inhibitor;BRAF inhibitor"
                    },
                    {
                        "alteration": "NF1:del;BRAF:."
                    },
                    {
                        "alteration": "NF1:.;BRAF:."
                    },
                    {
                        "mechanism_of_interaction": "Serine/threonine-protein kinase B-raf inhibitor"
                    },
                    {
                        "direct_interaction": "yes"
                    },
                    {
                        "specific_action_of_the_ligand": "Inhibition"
                    },
                    {
                        "endogenous_drug": "False"
                    },
                    {
                        "direct_interaction": "True"
                    },
                    {
                        "combination_therapy": "Vemurafenib + Panitumumab"
                    },
                    {
                        "combination_therapy": "Vemurafenib + Cetuximab"
                    },
                    {
                        "combination_therapy": "Vemurafenib + Cobimetinib"
                    },
                    {
                        "notes": "V600E mutation"
                    },
                    {
                        "response_type": "resistant"
                    },
                    {
                        "approval_status": "Preclinical - Cell culture"
                    },
                    {
                        "evidence_type": "Actionable"
                    },
                    {
                        "approval_status": "Preclinical"
                    },
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "approval_status": "Clinical Study"
                    },
                    {
                        "response_type": "decreased response"
                    },
                    {
                        "approval_status": "Phase II"
                    },
                    {
                        "approval_status": "Guideline"
                    },
                    {
                        "approval_status": "FDA approved"
                    },
                    {
                        "combination_therapy": "Vemurafenib + TW-37"
                    },
                    {
                        "combination_therapy": "PAC-1 + Trametinib + Vemurafenib"
                    },
                    {
                        "approval_status": "Phase I"
                    },
                    {
                        "combination_therapy": "Lapatinib + Vemurafenib"
                    },
                    {
                        "combination_therapy": "Vemurafenib + Gefitinib"
                    },
                    {
                        "combination_therapy": "Navitoclax + Vemurafenib"
                    },
                    {
                        "approval_status": "Preclinical - Cell line xenograft"
                    },
                    {
                        "combination_therapy": "Trametinib + Vemurafenib"
                    },
                    {
                        "response_type": "no benefit"
                    },
                    {
                        "combination_therapy": "Vemurafenib + SBI-060756"
                    },
                    {
                        "combination_therapy": "Vemurafenib + Erlotinib"
                    },
                    {
                        "combination_therapy": "DETD-35 + Vemurafenib"
                    },
                    {
                        "combination_therapy": "PAC-1 + Vemurafenib"
                    },
                    {
                        "combination_therapy": "PLX3397 + Vemurafenib"
                    },
                    {
                        "combination_therapy": "Selumetinib + Vemurafenib"
                    },
                    {
                        "combination_therapy": "Cetuximab + Selumetinib + Vemurafenib"
                    },
                    {
                        "combination_therapy": "BEZ235 + Vemurafenib"
                    },
                    {
                        "combination_therapy": "Vemurafenib + ZSTK474"
                    },
                    {
                        "approval_status": "Preclinical - Pdx"
                    },
                    {
                        "response_type": "conflicting"
                    },
                    {
                        "combination_therapy": "S63845 + Vemurafenib"
                    },
                    {
                        "combination_therapy": "Vemurafenib + Voruciclib"
                    },
                    {
                        "combination_therapy": "PET-16 + Vemurafenib"
                    },
                    {
                        "combination_therapy": "SAR260301 + Vemurafenib"
                    },
                    {
                        "combination_therapy": "Vemurafenib + Cetuximab + Irinotecan"
                    },
                    {
                        "approval_status": "Phase Ib/II"
                    },
                    {
                        "combination_therapy": "BKM120 + Vemurafenib"
                    },
                    {
                        "combination_therapy": "Atezolizumab + Vemurafenib + Cobimetinib"
                    },
                    {
                        "combination_therapy": "MK2206 + Vemurafenib"
                    },
                    {
                        "response_type": "predicted – sensitive"
                    },
                    {
                        "response_type": "predicted – resistant"
                    },
                    {
                        "clinical_status": "FDA-approved"
                    },
                    {
                        "pathway": "activation"
                    },
                    {
                        "variant_effect": "gain-of-function"
                    },
                    {
                        "clinical_status": "case report"
                    },
                    {
                        "clinical_status": "early trials"
                    },
                    {
                        "clinical_status": "late trials"
                    }
                ]
            },
            {
                "drug_name_primary": "Lenvatinib",
                "drug_chembl_id": "CHEMBL1289601",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Melanoma",
                        "id": 30010000004393
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": null,
                "drug_fda_approved": true,
                "attributes": [
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "approval_status": "Phase I"
                    },
                    {
                        "evidence_type": "Actionable"
                    }
                ]
            },
            {
                "drug_name_primary": "Voruciclib",
                "drug_chembl_id": "CHEMBL3545218",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Melanoma",
                        "id": 30010000004393
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": null,
                "drug_fda_approved": false,
                "attributes": [
                    {
                        "combination_therapy": "Vemurafenib + Voruciclib"
                    },
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "approval_status": "Phase I"
                    },
                    {
                        "evidence_type": "Actionable"
                    }
                ]
            },
            {
                "drug_name_primary": "Tubastatin A",
                "drug_chembl_id": "CHEMBL2018302",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Melanoma",
                        "id": 30010000004393
                    }
                ],
                "gene_symbol": "BRAF",
                "interaction_type": null,
                "drug_fda_approved": false,
                "attributes": [
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "approval_status": "Preclinical"
                    },
                    {
                        "evidence_type": "Actionable"
                    }
                ]
            },
            {
                "drug_name_primary": "Gedatolisib",
                "drug_chembl_id": "CHEMBL592445",
                "drug_immunotherapy": false,
                "drug_antineoplastic": null,
                "disease": [
                    {
                        "name": "Breast Cancer",
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                ]
            },
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            },
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                        "approval_status": "Preclinical - Cell culture"
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                ]
            },
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            },
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                ],
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                ]
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            },
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                "gene_symbol": "BRAF",
                "interaction_type": null,
                "drug_fda_approved": false,
                "attributes": [
                    {
                        "combination_therapy": "Binimetinib + BKM120"
                    },
                    {
                        "response_type": "sensitive"
                    },
                    {
                        "approval_status": "Preclinical - Cell culture"
                    },
                    {
                        "evidence_type": "Actionable"
                    },
                    {
                        "approval_status": "Preclinical - Cell line xenograft"
                    },
                    {
                        "combination_therapy": "Encorafenib + BKM120"
                    },
                    {
                        "combination_therapy": "BKM120 + Selumetinib"
                    },
                    {
                        "combination_therapy": "BKM120 + Vemurafenib"
                    },
                    {
                        "combination_therapy": "BKM120 + Trametinib"
                    }
                ]
            }
        ]
    },
    "cgd": {
        "version": "05_nov_2019",
        "pub_med_references": [
            16439621,
            16474404,
            17483702,
            17551924,
            18042262,
            18413255,
            18456719,
            19047498,
            19206169,
            20301303,
            20301365,
            20523244,
            21349766,
            21495173,
            22946697
        ],
        "condition": "Noonan syndrome; Cardiofaciocutaneous syndrome 1; LEOPARD syndrome 3",
        "inheritance": "AD",
        "age_group": "Pediatric",
        "intervention_categories": [
            "Cardiovascular",
            "Hematologic",
            "Oncologic"
        ],
        "comments": "Conditions may be frequently clinically recognized due to characteristic facial features as well as other manifestations",
        "intervention": null
    },
    "civic": {
        "version": "05_nov_2019",
        "items": [
            {
                "variant": "V600E AMPLIFICATION",
                "variant_summary": "Amplification of BRAF V600E has been shown to confer resistance to MEK inhibitors. For more information on the V600 locus, see the V600E entry.",
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/14",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    21098728
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "E",
                "evidence_statement": "COLO201 and COLO206F cells harboring BRAF V600E mutations were cloned to be MEK inhibitor (AZD6244 [selumetinib]) resistant. The mechanism of this resistance was shown to be amplification of the BRAF V600E gene. BRAF V600E amplification was observed in 1/11 colorectal cancer patient samples evaluated, indicating this subclone (28% of cells) would be MEK inhibitor resistant.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/92",
                "drugs": [
                    "Selumetinib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "4",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "AKAP9-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/184",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    15630448
                ],
                "clinical_significance": "Positive",
                "evidence_level": "B",
                "evidence_statement": "The AKAP9-BRAF fusion gene was found in 3/28 tumor samples of radiation-associated papillary thyroid carcinoma, and no samples of non-radiation associated papillary thyroid carcinoma. This fusion was associated with elevated BRAF kinase activity, similar to the V600E variant.",
                "evidence_type": "Diagnostic",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/462",
                "drugs": null,
                "transcripts": null,
                "representative_transcript": "ENST00000356239.3",
                "disease": "Thyroid Gland Papillary Carcinoma",
                "rating": "4",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "3969"
            },
            {
                "variant": "AGK-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/285",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    23890088
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "C",
                "evidence_statement": "BRAF fusion AGK-BRAF was associated with decreased sensitivity to vemurafenib and increased sensitivity to sorafenib in-vitro. A single patient with this fusion showed durable response to sorafenib.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/723",
                "drugs": [
                    "Sorafenib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000355413.4",
                "disease": "Melanoma",
                "rating": "2",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "1909"
            },
            {
                "variant": "AGK-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/285",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    23890088
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "D",
                "evidence_statement": "A melanoma cell line with AGK-BRAF in-frame fusion showed decreased sensitivity towards Vemurafenib in comparison with BRAF mutated (V600E) cell lines.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/724",
                "drugs": [
                    "Vemurafenib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000355413.4",
                "disease": "Melanoma",
                "rating": "2",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "1909"
            },
            {
                "variant": "PAPSS1-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/286",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    24345920
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "D",
                "evidence_statement": "BRAF-fusion in \"pan-negative\" melanomas were identified in TCGA data. Cell-lines with PAPSS1-BRAF fusion were resistant to treatment with Vemurafenib.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/725",
                "drugs": [
                    "Vemurafenib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000265174.4",
                "disease": "Melanoma",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "1909"
            },
            {
                "variant": "PAPSS1-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/286",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    24345920
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "D",
                "evidence_statement": "BRAF-fusion in \"pan-negative\" melanomas were identified in TCGA data. Cell-lines with a PAPSS1-BRAF fusion were resistant to treatment with Vemurafenib but sensitive to treatment with Trametinib. This fusion is believed to activate MAPK pathway signaling.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/726",
                "drugs": [
                    "Trametinib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000265174.4",
                "disease": "Melanoma",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "1909"
            },
            {
                "variant": "TRIM24-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/287",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    24345920
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "D",
                "evidence_statement": "A TRIM24-BRAF fusion was identified in a single patient with metastatic melanoma that was \"pan-negative\" for driver mutations. A cell-line (293H) ectopically expressing the TRIM24-BRAF fusion was found to be sensitive to the MEK-inhibitor Trametinib.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/727",
                "drugs": [
                    "Trametinib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000343526.4",
                "disease": "Melanoma",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "1909"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    22169769
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "D",
                "evidence_statement": "In this screen of 218 solid cancer cell lines, BRAF mutations were predictive of response to the MEK inhibitor GSK1120212. 26 of these cell lines had the BRAF V600E mutation, one cell line had a G469A mutation, one had G596R mutation and one had an unspecified mutation. Also of note, in RAF/RAS mutant colon cancer cell lines, co-occurring PIK3CA/PTEN mutations led to a cytostatic response rather than a cytotoxic response.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/936",
                "drugs": [
                    "Trametinib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Cancer",
                "rating": "4",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "162"
            },
            {
                "variant": "WILD TYPE",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/426",
                "variant_origin": null,
                "pub_med_references": [
                    24947927
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "B",
                "evidence_statement": "Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655. Among 12 patients with melanoma BRAF wild type and non-NRAS or NRAS unknown status, seven patients experienced partial response or stable disease.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/995",
                "drugs": [
                    "MEK Inhibitor RO4987655"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Melanoma",
                "rating": "2",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "1909"
            },
            {
                "variant": "DEL 485-490",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/522",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    26732095
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "D",
                "evidence_statement": "Cells harboring in-frame deletions in BRAF in the L485-P490 amino acid region were found to be sensitive to the RAF dimer inhibitor LY3009120, but not sensitive to the BRAF-selective inhibitors vemurafenib or dabrafenib. These deletions were observed in KRAS wildtype pancreatic, ovarian, NSCLC, and thyroid cancers. In three cell lines H2405 (NSCLC with L485-P490>Y), BxPC-3 (pancreatic with V487-P492>A), and OV-90 (ovarian with N486-P490del), BRAF deletion–mediated MAPK activation was found to be sensitive to LY3009120 as evidenced by dose-dependent inhibition of phospho-MEK and ERK and cell growth inhibition with IC50 values of 0.04, 0.087, and 0.007 μmol/L in these three cell lines. LY3009120, but not vemurafenib, also inhibited tumor growth of both H2405 and BxPC-3 cells xenografted into mice.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1267",
                "drugs": [
                    "Pan-RAF Inhibitor LY3009120"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Cancer",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "162"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    25673558
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "B",
                "evidence_statement": "A quantitative synthesis was performed on nine studies comparing treatment of metastatic colorectal cancer with cetuximab or panitumumab and chemotherapy, versus chemotherapy alone, or with other targeted inhibitors. It was found that in the patient subgroup with BRAF mutation (V600E in the majority of cases), there were no benefits to overall survival, progression free survival, or overall response rate with addition of cetuximab or panitumumab to treatment. This conclusion held in the first line treatment as well as general treatment setting.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Does Not Support",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1404",
                "drugs": [
                    "Cetuximab",
                    "Panitumumab"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "TRIM24-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/287",
                "variant_origin": null,
                "pub_med_references": [
                    24345920
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "D",
                "evidence_statement": "Foundation One NGS assay and targeted RNAseq identified PAPSS1-BRAF fusion in a melanoma sample. Further BRAF fusions (TRIM24-BRAF) were identified in TCGA and additional samples. Ectopic expression of engineered cDNA in 293H cells showed that trametinib led to reduced ERK1/2 phosphorylation in fusion positive cells whereas vemurafenib was not effective.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1416",
                "drugs": [
                    "Vemurafenib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000343526.4",
                "disease": "Skin Melanoma",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "8923"
            },
            {
                "variant": "PPFIBP2-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/617",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    26072686
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "C",
                "evidence_statement": "Case report of a 47year old female patient with metastatic melanoma (BRAF, NRAS, KIT negative). A PPFIBP2-BRAF fusion was identified from DNA from a brain metastasis (inton 3 of PPFIBP2 fused to intron 10 of BRAF). Trametinib was introduced and anemia and ECOG status improved. Imaging revealed a 90% decrease in extracranial and 19% decrease in intracranial metastases with no new metastases and no progressing sites at 6 weeks. Trametinib was stopped and pembrolizumab introduced at this time. Progressive disease was noted after 5 cycles of pembrolizumab but re-introduction of trametinib did not show an effect.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1570",
                "drugs": [
                    "Trametinib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000299492.4",
                "disease": "Skin Melanoma",
                "rating": "2",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "8923"
            },
            {
                "variant": "KIAA1549-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/618",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    26072686
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "C",
                "evidence_statement": "A 65 yr old male patient with metastatic acral lentiginous melanoma (BRAF, NRAS, KIT negative) was found to harbor a KIAA1549-BRAF (intron 15-intron 8) fusion in a subcutaneous metastasis sample after disease progression. Trametinib was started and fatigue and ECOG status improved but imaging revealed slight disease progression after 2 weeks (15 sites measurable, 9 stable, 6 progressive). No new metastases were identified. The patient was switched to pembrolizumab and major disease progression was noted.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1571",
                "drugs": [
                    "Trametinib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000440172.1",
                "disease": "Skin Melanoma",
                "rating": "1",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "8923"
            },
            {
                "variant": "BRAF-CUL1",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/656",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    26324360
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "C",
                "evidence_statement": "One patient with low-grade serous ovarian cancer had an in-frame fusion between the BRAF kinase domain and CUL1 identified by panel sequencing (MSK-IMPACT), with expression confirmed by whole-transcriptome sequencing. This patient with metastatic disease after treatment with carboplatin and paclitaxel, was enrolled onto a study of paclitaxel in combination with an oral MEK inhibitor and achieved a CR. She continued to receive therapy for 7 months, until discontinuation because of the development of pneumonitis. At publication, sustained CR had lasted > 18 months.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1662",
                "drugs": [
                    "Mitogen-Activated Protein Kinase Kinase Inhibitor"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Ovarian Serous Carcinoma",
                "rating": "2",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "0050933"
            },
            {
                "variant": "ZKSCAN1-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/657",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    26314551
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "C",
                "evidence_statement": "Analysis of BRAF fusions in 20,573 tumors, across 12 distinct tumor types. BRAF fusions were identified in 55 (0.3%) patients and enriched in spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers. Clinical data were available for two patients. Among them one 46-year old woman with spitzoid melanoma that  harbored  a ZKSCAN1-BRAF fusion responded to treatment with the MEK inhibitor trametinib. Subcutaneous  tumor  nodules  exhibited  clinical responses within 14 days of therapy, and her dominant bulky right lung metastases showed significant response by Day 45. Subsequent robotic-assisted lobectomy was able to remove the previously unresectable tumor with clean surgical margins.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1663",
                "drugs": [
                    "Trametinib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000426572.1",
                "disease": "Melanoma",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "1909"
            },
            {
                "variant": "KIAA1549-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/618",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    24422672
                ],
                "clinical_significance": "Sensitivity/Response",
                "evidence_level": "C",
                "evidence_statement": "A patient with a malignant spindle cell tumor of the chest wall treated as a soft tissue sarcoma was identified to harbor a KIAA1549-BRAF fusion. This patient responded to treatment with the pan-kinase inhibitor sorafenib in combination with bevacizumab and temsirolimus, achieving stable disease after 2 cycles extending into 11 cycles at which time she expired due to co-morbidities (acute myocardial infarction, hypotension). Of note, sequencing of 236 cancer-related genes identified CDKN2A A68fs*51, SUFU E283fs*3, MAP3K1 N325fs*3 and homozygous deletion of PTEN as well.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1664",
                "drugs": [
                    "Temsirolimus",
                    "Bevacizumab",
                    "Sorafenib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000440172.1",
                "disease": "Sarcoma",
                "rating": "2",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "1115"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    22586653
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "D",
                "evidence_statement": "A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1704",
                "drugs": [
                    "Cetuximab"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "2",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "AMPLIFICATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/1269",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    25673644
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "C",
                "evidence_statement": "Paired pre-treatment and post-progression tumor biopsies from BRAF-mutant CRC patients treated with RAF inhibitor combinations were analyzed. Alterations in MAPK pathway genes were found in resistant tumors not present in matched pre-treatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation.",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2929",
                "drugs": [
                    "Panitumumab",
                    "Dabrafenib"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    19603024
                ],
                "clinical_significance": "Poor Outcome",
                "evidence_level": "B",
                "evidence_statement": "This was a retrospective clinical study of 168 metastatic colorectal cancer patients who received first line chemotherapy (made up of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan) alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between BRAF mutation status in primary tumors and post treatment PFS. Of 168 patients, 155 had wildtype BRAF and 13 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation had a significantly worse outcome than patients expressing wildtype BRAF, regardless of first line chemotherapy regimen or use of monoclonal antibody treatment (Median PFS: 4.3 and 12.5 months, respectively; p <.0001).",
                "evidence_type": "Prognostic",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/6302",
                "drugs": null,
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    19603024
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "B",
                "evidence_statement": "This was a retrospective clinical study of 100 metastatic colorectal cancer patients who received FOLFOX (oxaliplatin + 5-fluorouracil + folinic acid) first-line therapy alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between BRAF mutation status in primary tumors and response to oxaliplatin-based first-line therapy, as measured by post treatment PFS. Of 100 patients, 94 had wildtype BRAF and 6 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation were significantly more resistant to oxaliplatin-based first-line therapy than patients with wildtype BRAF (Median PFS: 5.0 and 11. 7 months, respectively; p < .0001).",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/6303",
                "drugs": [
                    "Oxaliplatin"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    19603024
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "B",
                "evidence_statement": "This was a retrospective clinical study of 44 metastatic colorectal cancer patients who received FOLFIRI (5-Fluorouacil + Folinic acid + irinotecan) first-line therapy alone or with bevacizumab. It assessed the relationship between BRAF mutation status in primary tumors and response to irinotecan-based first line therapy, as measured by PFS. Of the 44 patients, 39 had wildtype BRAF and 5 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation were significantly more resistant to irinotecan-based first-line therapy than patients with wildtype BRAF (Median PFS: 3.5 and 12.8 months, respectively; p = .006).",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/6304",
                "drugs": [
                    "Irinotecan"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    19603024
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "B",
                "evidence_statement": "This was a retrospective clinical study of 97 metastatic colorectal cancer patients who received bevacizumab in conjunction with first-line chemotherapy (composed of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan). It assessed the relationship between BRAF mutation status in primary tumors and response to bevacizumab-containing first line chemotherapy, as measured by PFS. Of the 97 patients,89 had wildtype BRAF and 8 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation were significantly more resistant to bevacizumab-containing first-line chemotherapy than patients with wildtype BRAF (Median PFS: 4.2 and 12.5 months, respectively; p < .0001).",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/6305",
                "drugs": [
                    "Bevacizumab"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    19603024
                ],
                "clinical_significance": "Resistance",
                "evidence_level": "B",
                "evidence_statement": "This was a retrospective clinical study of 92 metastatic colorectal cancer patients who received cetuximab in conjunction with salvage chemotherapy (refractory to at least one line of treatment). Salvage chemotherapy was composed of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan. The study assessed the relationship between BRAF mutation status in primary tumors and response to cetuximab-containing salvage chemotherapy, as measured by PFS. Of the 92 patients, 83 had wildtype BRAF and 9 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation were significantly more resistant to cetuximab-containing salvage chemotherapy than patients with wildtype BRAF (Median PFS: 2.0 and 3.9, respectively; p = .0005).",
                "evidence_type": "Predictive",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/6306",
                "drugs": [
                    "Cetuximab"
                ],
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    19603024
                ],
                "clinical_significance": "Poor Outcome",
                "evidence_level": "B",
                "evidence_statement": "This was a retrospective clinical study of 168 metastatic colorectal cancer patients who received first line chemotherapy (made up of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan) alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between BRAF mutation status in primary tumors and post treatment OS. Of 168 patients, 155 had wildtype BRAF and 13 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation had a significantly worse outcome than patients expressing wildtype BRAF, regardless of first line chemotherapy regimen or use of monoclonal antibody treatment (Median OS: 10.9 and 40.5 months, respectively; p <.0001).",
                "evidence_type": "Prognostic",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/6307",
                "drugs": null,
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "KIAA1549-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/618",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    23817572
                ],
                "clinical_significance": "Positive",
                "evidence_level": "B",
                "evidence_statement": "Genetic alterations in pilocytic astrocytoma (PA) were evaluated. Whole-genome sequencing of normal (blood) and tumor samples (n=96) was performed along with corresponding RNA-Seq (n=73) and mate-pair (MP) sequencing (n=68).  Several known events activating the MAPK pathway were identified with KIAA1549-BRAF fusion being the most frequent variants (70 of 96 cases, 73%). Importantly, all but one of the cerebellar PA harbored a BRAF fusion (47 of 48 samples, 98%) with this one exception having a KRAS alteration.",
                "evidence_type": "Diagnostic",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/7148",
                "drugs": null,
                "transcripts": null,
                "representative_transcript": "ENST00000440172.1",
                "disease": "Pilocytic Astrocytoma",
                "rating": "5",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "4851"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    21641636
                ],
                "clinical_significance": "Poor Outcome",
                "evidence_level": "B",
                "evidence_statement": "In the Medical Research Council (MRC) COIN trial, ISRCTN27286448, patients who presented with advanced colorectal cancer were randomly assigned to chemotherapy (oxaliplatin and fluoropyrimidine; arm A), or chemotherapy plus cetuximab (arm B). Median overall survival was found to differ by mutation, regardless of treatment. Median overall survival was 8.8 months (IQR 4.5-27) for patients with BRAF variants, 14.4 months (IQR 8.5-24.0) for patients with KRAS variants, and 20.1 months (IQR 11.5-31.7) for wildtype patients. BRAF mutations were found in 102/1291 samples (7.90%), and of these, 12 were D594G and 90 V600E.",
                "evidence_type": "Prognostic",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/7158",
                "drugs": null,
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "4",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "MUTATION",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/399",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    24112392
                ],
                "clinical_significance": "Poor Outcome",
                "evidence_level": "B",
                "evidence_statement": "A meta analysis was performed using data from 21 published studies (n = 9885 patients) to assess prognostic value of BRAF mutations in colorectal cancer. When evaluating 14 studies (n = 7778 patients), the odds ratio (OR) of a proximal lesion, which is associated with greater mortality in colon cancer, was increased for patients with BRAF mutations (OR 5.222, 95% CI 3.801–7.174, P < 0.001). When evaluating 4 studies (n = 1526 patients), the odds ratio of T4 tumors, which indicates tumor growth past bowel lining, was increased for patients with BRAF mutations (OR 1.761, 95% CI 1.164–2.663, P = 0.007). When evaluating 8 studies (n = 2786 patients), the odds ratio of poor tumor differentiation was increased in patients with BRAF mutations (OR 3.816, 95% CI 2.714–5.365, P < 0.001). These results support that BRAF mutations indicate poor prognosis for patients with colorectal cancer.",
                "evidence_type": "Prognostic",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/7159",
                "drugs": null,
                "transcripts": null,
                "representative_transcript": "ENST00000288602.6",
                "disease": "Colorectal Cancer",
                "rating": "4",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "9256"
            },
            {
                "variant": "KIAA1549-BRAF",
                "variant_summary": null,
                "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/618",
                "variant_origin": "Somatic",
                "pub_med_references": [
                    18974108
                ],
                "clinical_significance": "Gain of Function",
                "evidence_level": "D",
                "evidence_statement": "This study identified a novel rearrangement event between the uncharacterized gene KIAA-1549 and BRAF in 66% (29 of 44) of pilocytic astrocytoma. The fusion gene was shown to delete the N-terminal BRAF auto-regulatory domain which in vitro assays indicated leads to constitutive activation of BRAF. Cos7 cells were transfected with two isoforms of KIAA1549-BRAF (both exon 16:exon 9), BRAF V600E, or wildtype BRAF and evaluated activity via BRAF kinase assay. Both fusion isoforms showed similar or higher kinase activity than V600E transfected cells. NIH3T3 cells transfected with V600E or the short fusion isoform also demonstrated anchorage-independent growth in soft agarose.",
                "evidence_type": "Functional",
                "evidence_status": "accepted",
                "evidence_direction": "Supports",
                "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/7337",
                "drugs": null,
                "transcripts": null,
                "representative_transcript": "ENST00000440172.1",
                "disease": "Pilocytic Astrocytoma",
                "rating": "3",
                "gene": "BRAF",
                "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/5",
                "entrez_id": "673",
                "doid": "4851"
            }
        ]
    },
    "dbnsfp_genes": {
        "version": "v3_4",
        "items": [
            {
                "kegg": {
                    "id": [
                        "hsa04010",
                        "hsa04012",
                        "hsa04150",
                        "hsa04510",
                        "hsa04650",
                        "hsa04720",
                        "hsa04730",
                        "hsa04810",
                        "hsa04910",
                        "hsa05210",
                        "hsa05211",
                        "hsa05212",
                        "hsa05213",
                        "hsa05214",
                        "hsa05215",
                        "hsa05216",
                        "hsa05218",
                        "hsa05219",
                        "hsa05220",
                        "hsa05221",
                        "hsa05223"
                    ],
                    "full": [
                        "MAPK signaling pathway",
                        "ErbB signaling pathway",
                        "mTOR signaling pathway",
                        "Focal adhesion",
                        "Natural killer cell mediated cytotoxicity",
                        "Long-term potentiation",
                        "Long-term depression",
                        "Regulation of actin cytoskeleton",
                        "Insulin signaling pathway",
                        "Colorectal cancer",
                        "Renal cell carcinoma",
                        "Pancreatic cancer",
                        "Endometrial cancer",
                        "Glioma",
                        "Prostate cancer",
                        "Thyroid cancer",
                        "Melanoma",
                        "Bladder cancer",
                        "Chronic myeloid leukemia",
                        "Acute myeloid leukemia",
                        "Non-small cell lung cancer"
                    ]
                },
                "expressions_rpkm": {
                    "whole_blood": 3.30913,
                    "vagina": 3.7550499999999998,
                    "uterus": 3.57055,
                    "thyroid": 4.1325899999999995,
                    "testis": 13.5643,
                    "stomach": 2.46463,
                    "spleen": 1.67521,
                    "small_intestine___terminal_ileum": 2.04278,
                    "skin___sun_exposed__lower_leg": 3.32083,
                    "skin___not_sun_exposed__suprapubic": 3.534,
                    "prostate": 3.30376,
                    "pituitary": 2.7909,
                    "pancreas": 1.7761600000000002,
                    "ovary": 3.8519399999999995,
                    "nerve___tibial": 3.2297200000000004,
                    "muscle___skeletal": 2.208,
                    "minor_salivary_gland": 2.6647000000000003,
                    "brain___hypothalamus": 1.4779599999999997,
                    "brain___hippocampus": 1.24968,
                    "brain___frontal_cortex__ba9": 1.7672100000000002,
                    "brain___cortex": 1.50765,
                    "brain___cerebellum": 2.4791,
                    "brain___cerebellar_hemisphere": 3.15838,
                    "brain___caudate__basal_ganglia": 1.4356599999999997,
                    "brain___anterior_cingulate_cortex__ba24": 1.4579499999999999,
                    "brain___amygdala": 1.21044,
                    "bladder": 5.397799999999999,
                    "adipose___visceral__omentum": 3.23132,
                    "adipose___subcutaneous": 3.2558599999999998,
                    "adrenal_gland": 2.0102599999999997,
                    "artery___aorta": 2.7535600000000002,
                    "artery___coronary": 2.65846,
                    "artery___tibial": 3.31351,
                    "brain___nucleus_accumbens__basal_ganglia": 1.4737699999999998,
                    "brain___putamen__basal_ganglia": 1.1640400000000002,
                    "brain___spinal_cord__cervicalc_1": 1.4798799999999999,
                    "brain___substantia_nigra": 1.2614299999999998,
                    "breast___mammary_tissue": 3.58406,
                    "cells___ebv_transformed_lymphocytes": 8.48165,
                    "cells___transformed_fibroblasts": 3.8170399999999995,
                    "cervix___ectocervix": 3.53537,
                    "cervix___endocervix": 3.58384,
                    "colon___sigmoid": 2.7109900000000002,
                    "colon___transverse": 2.17616,
                    "esophagus___gastroesophageal_junction": 2.57497,
                    "esophagus___mucosa": 3.02526,
                    "esophagus___muscularis": 2.71157,
                    "fallopian_tube": 2.34975,
                    "heart___atrial_appendage": 2.67455,
                    "heart___left_ventricle": 1.84277,
                    "kidney___cortex": 2.4169499999999995,
                    "liver": 1.34584,
                    "lung": 3.8372399999999995
                },
                "gene_symbol": "BRAF"
            }
        ]
    },
    "exac_genes": {
        "version": "18_sep_2018",
        "items": [
            {
                "prec": 2.1804000000000003e-05,
                "pnull": 3.88216e-14,
                "pli": 0.999978,
                "syn_z": -0.006721120000000002,
                "mis_z": 3.9913399999999997,
                "cnv_score": 0.5920480000000001,
                "segdups": 0,
                "flag": false
            }
        ]
    },
    "pub_med_articles": {
        "28650561": {
            "abstract": "RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan-like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported. Here, we describe patients with craniosynostosis and Noonan syndrome due to de novo mutations in PTPN11 and patients with craniosynostosis and CFC syndrome due to de novo mutations in BRAF or KRAS. All of these patients had cranial deformities in addition to the typical phenotypes of CFC syndrome and Noonan syndrome. In RASopathy, patients with cranial deformities, further assessments may be necessary to look for craniosynostosis. Future studies should attempt to elucidate the pathogenic mechanism responsible for craniosynostosis mediated by the RAS/MAPK signaling pathway.",
            "authors": [
                "Ueda, K",
                "Yaoita, M",
                "Niihori, T",
                "Aoki, Y",
                "Okamoto, N"
            ],
            "is_common_article": false,
            "date_published": 20170900,
            "date_completed": 20171130,
            "format": "Article",
            "pub_med_id": 28650561,
            "title": "Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype.",
            "journal": "American journal of medical genetics. Part A",
            "journal_abbreviation": "Am. J. Med. Genet. A",
            "journal_issue": "volume:173, issue:9"
        },
        "26530882": {
            "abstract": "Some studies have demonstrated that familial non-medullary thyroid cancer (FNMTC) has a more aggressive clinical behavior compared to sporadic NMTC (SNMTC). However, FNMTC is difficult to differentiate from SNMTC by the morphology and immunohistochemistry. Although genes responsible for FNMTC were unclear, screening for rare germline mutations on known important tumor suppressor genes might offer more insights on predicting susceptibility to FNMTC. Here, a customized panel was designed to capture all exons of 31 cancer susceptive genes possibly related to FNMTC. Using next-generation sequencing we performed deep sequencing to achieve 500× coverage of the targeted regions. At the end 45 variants were identified in 29 of 47 familial patients and 6 of 16 sporadic patients. Notably, several germline mutations were found matching between paired FNMTC patients from the same family, including APC L292F and A2778S, BRAF D22N, MSH6 G355S and A36V, MSH2 L719F, MEN1 G508D, BRCA1 SS955S, BRCA2 G2508S, and a GNAS inframe insertion. We demonstrated a novel approach to help diagnose and elucidate the genetic cause of the FNMTC patients, and assess whether their family members are exposed to a higher genetic risk. The findings would also provide insights on monitoring the potential second cancers for thyroid cancer patients.",
            "authors": [
                "Yu, Y",
                "Dong, L",
                "Li, D",
                "Chuai, S",
                "Wu, Z",
                "Zheng, X",
                "Cheng, Y",
                "Han, L",
                "Yu, J",
                "Gao, M"
            ],
            "is_common_article": false,
            "date_published": 20151104,
            "date_completed": 20160928,
            "format": "Article",
            "pub_med_id": 26530882,
            "title": "Targeted DNA Sequencing Detects Mutations Related to Susceptibility among Familial Non-medullary Thyroid Cancer.",
            "journal": "Scientific reports",
            "journal_abbreviation": "Sci Rep",
            "journal_issue": "volume:5"
        },
        "26324360": {
            "abstract": "PURPOSE\nNo effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor.\n\nPATIENTS AND METHODS\nNext-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed.\n\nRESULTS\nAnalysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor-based combination therapy.\n\nCONCLUSION\nAlterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease.",
            "authors": [
                "Grisham, RN",
                "Sylvester, BE",
                "Won, H",
                "McDermott, G",
                "DeLair, D",
                "Ramirez, R",
                "Yao, Z",
                "Shen, R",
                "Dao, F",
                "Bogomolniy, F",
                "Makker, V",
                "Sala, E",
                "Soumerai, TE",
                "Hyman, DM",
                "Socci, ND",
                "Viale, A",
                "Gershenson, DM",
                "Farley, J",
                "Levine, DA",
                "Rosen, N",
                "Berger, MF",
                "Spriggs, DR",
                "Aghajanian, CA",
                "Solit, DB",
                "Iyer, G"
            ],
            "is_common_article": false,
            "date_published": 20151201,
            "date_completed": 20160308,
            "format": "Article",
            "pub_med_id": 26324360,
            "title": "Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer.",
            "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
            "journal_abbreviation": "J. Clin. Oncol.",
            "journal_issue": "volume:33, issue:34"
        },
        "26314551": {
            "abstract": "Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 (0.3%) of 20,573 tumors, across 12 distinct tumor types, including 20 novel BRAF fusions. These comprised 29 unique 5' fusion partners, of which 31% (9) were known and 69% (20) were novel. BRAF fusions included 3% (14/531) of melanomas; 2% (15/701) of gliomas; 1.0% (3/294) of thyroid cancers; 0.3% (3/1,062) pancreatic carcinomas; 0.2% (8/4,013) nonsmall-cell lung cancers and 0.2% (4/2,154) of colorectal cancers, and were enriched in pilocytic (30%) vs. nonpilocytic gliomas (1%; p < 0.0001), Spitzoid (75%) vs. nonSpitzoid melanomas (1%; p = 0.0001), acinar (67%) vs. nonacinar pancreatic cancers (<1%; p < 0.0001) and papillary (3%) vs. nonpapillary thyroid cancers (0%; p < 0.03). Clinical responses to trametinib and sorafenib are presented. In conclusion, BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms, but enriched in Spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers.",
            "authors": [
                "Ross, JS",
                "Wang, K",
                "Chmielecki, J",
                "Gay, L",
                "Johnson, A",
                "Chudnovsky, J",
                "Yelensky, R",
                "Lipson, D",
                "Ali, SM",
                "Elvin, JA",
                "Vergilio, JA",
                "Roels, S",
                "Miller, VA",
                "Nakamura, BN",
                "Gray, A",
                "Wong, MK",
                "Stephens, PJ"
            ],
            "is_common_article": false,
            "date_published": 20160215,
            "date_completed": 20160531,
            "format": "Article",
            "pub_med_id": 26314551,
            "title": "The distribution of BRAF gene fusions in solid tumors and response to targeted therapy.",
            "journal": "International journal of cancer",
            "journal_abbreviation": "Int. J. Cancer",
            "journal_issue": "volume:138, issue:4"
        },
        "26072686": {
            "authors": [
                "Menzies, AM",
                "Yeh, I",
                "Botton, T",
                "Bastian, BC",
                "Scolyer, RA",
                "Long, GV"
            ],
            "is_common_article": false,
            "date_published": 20150900,
            "date_completed": 20160622,
            "format": "Article",
            "pub_med_id": 26072686,
            "title": "Clinical activity of the MEK inhibitor trametinib in metastatic melanoma containing BRAF kinase fusion.",
            "journal": "Pigment cell & melanoma research",
            "journal_abbreviation": "Pigment Cell Melanoma Res",
            "journal_issue": "volume:28, issue:5"
        },
        "25673644": {
            "abstract": "UNLABELLED\nBRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance. To identify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations. We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity, but an ERK inhibitor could suppress MAPK activity and overcome resistance. Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.\n\nSIGNIFICANCE\nRAF inhibitor combinations represent promising approaches in clinical development for BRAF-mutant colorectal cancer. Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling, highlighting the critical dependence of BRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance.",
            "authors": [
                "Ahronian, LG",
                "Sennott, EM",
                "Van Allen, EM",
                "Wagle, N",
                "Kwak, EL",
                "Faris, JE",
                "Godfrey, JT",
                "Nishimura, K",
                "Lynch, KD",
                "Mermel, CH",
                "Lockerman, EL",
                "Kalsy, A",
                "Gurski, JM",
                "Bahl, S",
                "Anderka, K",
                "Green, LM",
                "Lennon, NJ",
                "Huynh, TG",
                "Mino-Kenudson, M",
                "Getz, G",
                "Dias-Santagata, D",
                "Iafrate, AJ",
                "Engelman, JA",
                "Garraway, LA",
                "Corcoran, RB"
            ],
            "is_common_article": false,
            "date_published": 20150400,
            "date_completed": 20160112,
            "format": "Article",
            "pub_med_id": 25673644,
            "title": "Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations.",
            "journal": "Cancer discovery",
            "journal_abbreviation": "Cancer Discov",
            "journal_issue": "volume:5, issue:4"
        },
        "25673558": {
            "abstract": "BACKGROUND\nWild type RAS (RAS-wt) status is predictive of the activities of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab (C) and panitumumab (P). We examined the impact of C and P on progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) in advanced colorectal cancer (CRC) patients who have RAS-wt/BRAF-mutant (BRAF-mut) status.\n\nMETHODS\nRandomised trials that compared C or P plus chemotherapy (or C or P monotherapy) with standard therapy or best supportive care (BSC) were included. We used published hazard ratios (HRs) if they were available, or we derived treatment estimates from other survival data. Pooled estimates of the treatment efficacy of anti-EGFR-based therapy with C or P for the RAS-wt/BRAF-mut subgroup were calculated with the random-effect inverse variance weighted method. All statistical tests were two-sided.\n\nRESULTS\nNine phase III trials and one phase II trial (six first-line and two second-line trials, plus two trials involving chemorefractory patients), that included 463 RAS-wt/BRAF-mut CRC patients, were analysed. Overall, the addition of C or P treatment in the BRAF-mut subgroup did not significantly improve PFS (HR, 0.88; 95% confidence interval (CI), 0.67-1.14; p=0.33), OS (HR, 0.91; 95% CI, 0.62-1.34; p=0.63) and ORR (relative risk, 1.31; 95% CI 0.83-2.08, p=0.25) compared with control regimens.\n\nCONCLUSIONS\nC- or P-based therapy did not increase the benefit of standard therapy or the BSC in RAS-wt/BRAF-mut CRC patients. These findings support BRAF mutation assessment before initiation of treatment with anti-EGFR monoclonal antibodies.",
            "authors": [
                "Pietrantonio, F",
                "Petrelli, F",
                "Coinu, A",
                "Di Bartolomeo, M",
                "Borgonovo, K",
                "Maggi, C",
                "Cabiddu, M",
                "Iacovelli, R",
                "Bossi, I",
                "Lonati, V",
                "Ghilardi, M",
                "de Braud, F",
                "Barni, S"
            ],
            "is_common_article": false,
            "date_published": 20150300,
            "date_completed": 20150512,
            "format": "Article",
            "pub_med_id": 25673558,
            "title": "Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis.",
            "journal": "European journal of cancer (Oxford, England : 1990)",
            "journal_abbreviation": "Eur. J. Cancer",
            "journal_issue": "volume:51, issue:5"
        },
        "24947927": {
            "abstract": "PURPOSE\nThis phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor.\n\nEXPERIMENTAL DESIGN\nWe undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added.\n\nRESULTS\nNinety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications.\n\nCONCLUSIONS\nSafety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251-61. ©2014 AACR.",
            "authors": [
                "Zimmer, L",
                "Barlesi, F",
                "Martinez-Garcia, M",
                "Dieras, V",
                "Schellens, JH",
                "Spano, JP",
                "Middleton, MR",
                "Calvo, E",
                "Paz-Ares, L",
                "Larkin, J",
                "Pacey, S",
                "Venturi, M",
                "Kraeber-Bodéré, F",
                "Tessier, JJ",
                "Eberhardt, WE",
                "Paques, M",
                "Guarin, E",
                "Meresse, V",
                "Soria, JC"
            ],
            "is_common_article": false,
            "date_published": 20140815,
            "date_completed": 20151013,
            "format": "Article",
            "pub_med_id": 24947927,
            "title": "Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations.",
            "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
            "journal_abbreviation": "Clin. Cancer Res.",
            "journal_issue": "volume:20, issue:16"
        },
        "19206169": {
            "abstract": "Noonan, LEOPARD, and cardiofaciocutaneous syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS-mitogen-activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N=270), LS (N=6), and CFCS (N=33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (52%), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer-associated defects. NS-causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer-associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions.",
            "authors": [
                "Sarkozy, A",
                "Carta, C",
                "Moretti, S",
                "Zampino, G",
                "Digilio, MC",
                "Pantaleoni, F",
                "Scioletti, AP",
                "Esposito, G",
                "Cordeddu, V",
                "Lepri, F",
                "Petrangeli, V",
                "Dentici, ML",
                "Mancini, GM",
                "Selicorni, A",
                "Rossi, C",
                "Mazzanti, L",
                "Marino, B",
                "Ferrero, GB",
                "Silengo, MC",
                "Memo, L",
                "Stanzial, F",
                "Faravelli, F",
                "Stuppia, L",
                "Puxeddu, E",
                "Gelb, BD",
                "Dallapiccola, B",
                "Tartaglia, M"
            ],
            "is_common_article": false,
            "date_published": 20090400,
            "date_completed": 20090706,
            "format": "Article",
            "pub_med_id": 19206169,
            "title": "Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.",
            "journal": "Human mutation",
            "journal_abbreviation": "Hum. Mutat.",
            "journal_issue": "volume:30, issue:4"
        },
        "20301303": {
            "abstract": "CLINICAL CHARACTERISTICS\nNoonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.\n\nDIAGNOSIS/TESTING\nNS is diagnosed on clinical grounds by observation of key features. Affected individuals have normal chromosome studies. Molecular genetic testing identifies a pathogenic variant in PTPN11 in 50% of affected individuals, SOS1 in approximately 13%, RAF1 and RIT1 each in 5%, and KRAS in fewer than 5%. Other genes in which pathogenic variants have been reported to cause Noonan syndrome in fewer than 1% of cases include NRAS, BRAF, and MAP2K1. Several additional genes associated with a Noonan-syndrome-like phenotype in fewer than ten individuals have been identified.\n\nMANAGEMENT\nTreatment of manifestations: Cardiovascular anomalies in NS are usually treated as in the general population. Developmental disabilities are addressed by early intervention programs and individualized education strategies. Treatment for serious bleeding is guided by knowledge of the specific factor deficiency or platelet aggregation anomaly. Growth hormone (GH) treatment increases growth velocity. Surveillance: Monitoring of anomalies found in any system, especially cardiovascular abnormalities.\n\nGENETIC COUNSELING\nNS is inherited in an autosomal dominant manner. Although many individuals with NS have a de novo pathogenic variant, an affected parent is recognized in 30%-75% of families. The risk to sibs of a proband depends on the genetic status of the parents. If a parent is affected, the risk is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%). Each child of an individual with Noonan syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing is possible if the NS-related pathogenic variant has been identified in an affected family member.",
            "authors": [
                "Pagon, RA",
                "Adam, MP",
                "Ardinger, HH",
                "Wallace, SE",
                "Amemiya, A",
                "Bean, LJH",
                "Bird, TD",
                "Fong, CT",
                "Mefford, HC",
                "Smith, RJH",
                "Stephens, K"
            ],
            "is_common_article": false,
            "format": "Book",
            "date_published": 19930000,
            "pub_med_id": 20301303,
            "date_completed": 20160000,
            "publisher": "University of Washington, Seattle",
            "title": "GeneReviews(®)"
        },
        "23009221": {
            "authors": [
                "Alonso, CM",
                "Such, E",
                "Gómez-Seguí, I",
                "Cervera, J",
                "Martínez-Cuadrón, D",
                "Luna, I",
                "Ibáñez, M",
                "López-Pavía, M",
                "Vera, B",
                "Navarro, I",
                "Senent, L",
                "Sanz Alonso, MA"
            ],
            "is_common_article": false,
            "date_published": 20130500,
            "date_completed": 20131104,
            "format": "Article",
            "pub_med_id": 23009221,
            "title": "BRAF V600E mutation in adult acute lymphoblastic leukemia.",
            "journal": "Leukemia & lymphoma",
            "journal_abbreviation": "Leuk. Lymphoma",
            "journal_issue": "volume:54, issue:5"
        },
        "18974108": {
            "abstract": "Brain tumors are the most common solid tumors of childhood, and pilocytic astrocytomas (PA) are the most common central nervous system tumor in 5 to 19 year olds. Little is known about the genetic alterations underlying their development. Here, we describe a tandem duplication of approximately 2 Mb at 7q34 occurring in 66% of PAs. This rearrangement, which was not observed in a series of 244 higher-grade astrocytomas, results in an in-frame fusion gene incorporating the kinase domain of the BRAF oncogene. We further show that the resulting fusion protein has constitutive BRAF kinase activity and is able to transform NIH3T3 cells. This is the first report of BRAF activation through rearrangement as a frequent feature in a sporadic tumor. The frequency and specificity of this change underline its potential both as a therapeutic target and as a diagnostic tool.",
            "authors": [
                "Jones, DT",
                "Kocialkowski, S",
                "Liu, L",
                "Pearson, DM",
                "Bäcklund, LM",
                "Ichimura, K",
                "Collins, VP"
            ],
            "is_common_article": false,
            "date_published": 20081101,
            "date_completed": 20081208,
            "format": "Article",
            "pub_med_id": 18974108,
            "title": "Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas.",
            "journal": "Cancer research",
            "journal_abbreviation": "Cancer Res.",
            "journal_issue": "volume:68, issue:21"
        },
        "18456719": {
            "abstract": "BACKGROUND\nNoonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFC) are related disorders associated with disrupted RAS/RAF/MEK/ERK signalling. NS, characterised by facial dysmorphism, congenital heart defects and short stature, is caused by mutations in the genes PTPN11, SOS1, KRAS and RAF1. CFC is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2.\n\nMETHODS\nA comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated patients without mutations in PTPN11 is presented.\n\nRESULTS\nMutations were identified in seven patients with CFC (two in BRAF, one in KRAS, one in MEK1, two in MEK2 and one in SOS1). Two mutations were novel: MEK1 E203Q and MEK2 F57L. The SOS1 E433K mutation, identified in a patient diagnosed with CFC, has previously been reported in patients with NS. In one patient with NS, we also identified a mutation, BRAF K499E, that has previously been reported in patients with CFC. We thus suggest involvement of BRAF in the pathogenesis of NS also.\n\nCONCLUSIONS\nTaken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even represent allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, for example, NS-PTPN11-associated or CFC-BRAF-associated syndromes after the genetic defect has been established, as this may affect the prognosis and treatment of the patients.",
            "authors": [
                "Nyström, AM",
                "Ekvall, S",
                "Berglund, E",
                "Björkqvist, M",
                "Braathen, G",
                "Duchen, K",
                "Enell, H",
                "Holmberg, E",
                "Holmlund, U",
                "Olsson-Engman, M",
                "Annerén, G",
                "Bondeson, ML"
            ],
            "is_common_article": false,
            "date_published": 20080800,
            "date_completed": 20080919,
            "format": "Article",
            "pub_med_id": 18456719,
            "title": "Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders.",
            "journal": "Journal of medical genetics",
            "journal_abbreviation": "J. Med. Genet.",
            "journal_issue": "volume:45, issue:8"
        },
        "18413255": {
            "abstract": "Cardio-facio-cutaneous syndrome (CFC) is a sporadic, complex developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, growth deficiency, hypotonia, and developmental delay. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterogeneous de novo germline mutations in B-Raf mutant proteins, MEK1 and MEK2. Approximately 75% of individuals with CFC have mutations in BRAF. In vitro functional studies demonstrate that many of these mutations confer increase activity upon the mutant protein as compared to the wildtype protein. However, as is seen cancer, some of the B-Raf mutant proteins are kinase impaired. Western blot analyses corroborate kinase assays as determined by mutant proteins phosphorylating downstream effectors MEK and ERK. Approximately 25% of individuals with CFC have mutations in either MEK1 or MEK2 that lead to increased MEK kinase activity as judged by increased phosphorylation of its downstream effector ERK. Unlike BRAF, no somatic mutations have ever been identified in MEK genes. The identification of novel germline BRAF and MEK mutations in CFC will help understand the pathophysiology of this syndrome. Furthermore, it will also provide insight to the normal function of B-Raf and MEK, and contribute to the knowledge of the role of the MAPK pathway in cancer. Since the MAPK pathway has been studied intensively in the context of cancer, numerous therapeutics that specifically target this pathway may merit investigation in this population of patients.",
            "authors": [
                "Rodriguez-Viciana, P",
                "Rauen, KA"
            ],
            "is_common_article": false,
            "date_published": 20080000,
            "date_completed": 20080619,
            "format": "Article",
            "pub_med_id": 18413255,
            "title": "Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.",
            "journal": "Methods in enzymology",
            "journal_abbreviation": "Meth. Enzymol.",
            "journal_issue": "volume:438"
        },
        "22230299": {
            "abstract": "The spectrum of underlying molecular abnormalities of clinically and biologically heterogeneous chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL) has yet to be identified. While whole genome sequencing has identified several genes implicated in the pathogenesis and progression of CLL, the molecular lesions in a substantial proportion of patients remain to be elucidated. The incidence of the BRAF V600E mutation, widely implicated in solid tumours and other B-cell malignancies, was sought in a cohort of patients with CLL and related disorders. One CLL patient and one patient with B-prolymphocytic leukaemia (PLL) were found to harbour this mutation. Although present at a low frequency, the finding of BRAF V600E has biological and clinical implications for CLL and PLL.",
            "authors": [
                "Langabeer, SE",
                "Quinn, F",
                "O'Brien, D",
                "McElligott, AM",
                "Kelly, J",
                "Browne, PV",
                "Vandenberghe, E"
            ],
            "is_common_article": false,
            "date_published": 20120400,
            "date_completed": 20120411,
            "format": "Article",
            "pub_med_id": 22230299,
            "title": "Incidence of the BRAF V600E mutation in chronic lymphocytic leukaemia and prolymphocytic leukaemia.",
            "journal": "Leukemia research",
            "journal_abbreviation": "Leuk. Res.",
            "journal_issue": "volume:36, issue:4"
        },
        "18042262": {
            "abstract": "Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1- and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.",
            "authors": [
                "Schulz, AL",
                "Albrecht, B",
                "Arici, C",
                "van der Burgt, I",
                "Buske, A",
                "Gillessen-Kaesbach, G",
                "Heller, R",
                "Horn, D",
                "Hübner, CA",
                "Korenke, GC",
                "König, R",
                "Kress, W",
                "Krüger, G",
                "Meinecke, P",
                "Mücke, J",
                "Plecko, B",
                "Rossier, E",
                "Schinzel, A",
                "Schulze, A",
                "Seemanova, E",
                "Seidel, H",
                "Spranger, S",
                "Tuysuz, B",
                "Uhrig, S",
                "Wieczorek, D",
                "Kutsche, K",
                "Zenker, M"
            ],
            "is_common_article": false,
            "date_published": 20080100,
            "date_completed": 20080229,
            "format": "Article",
            "pub_med_id": 18042262,
            "title": "Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome.",
            "journal": "Clinical genetics",
            "journal_abbreviation": "Clin. Genet.",
            "journal_issue": "volume:73, issue:1"
        },
        "17551924": {
            "abstract": "Because Cardio-facio-cutaneous (CFC) syndrome has significant phenotypic overlap with Costello syndrome, it may be difficult to establish the diagnosis on a clinical basis. The recent discoveries of germline HRAS mutations in patients with Costello syndrome and mutations in BRAF, MEK1, and MEK2 in CFC syndrome uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the affected gene products within the MAP kinase pathway. We evaluated a series of patients who were either clinically diagnosed with Costello syndrome, or in whom the diagnoses of both Costello and CFC syndromes were considered. After excluding mutations in HRAS, we identified eight changes in BRAF and five in MEK1. Five mutations are novel, and all changes occurred de novo among those triads tested. A review of the clinical abnormalities showed important differences between patients with either a BRAF or MEK1 mutation, and those previously reported with an HRAS mutation. Statistical significance was achieved, despite the relatively small number of patients with BRAF and MEK1 mutations reported here, for polyhydramnios, growth hormone deficiency and the presence of more than one papilloma, which were less common in CFC compared to HRAS mutation positive patients. Although both CFC and Costello syndrome are characterized by cardiac abnormalities in about three-fourths of patients, the pattern of congenital heart defects (CHD), hypertrophic cardiomyopathy (HCM), and tachycardia differs somewhat. CHD, especially pulmonic stenosis associated with a secundum-type atrial septal defect, are more common in CFC than Costello syndrome (P = 0.02). Atrial tachycardia is less frequent in CFC patients with BRAF or MEK1 mutations, compared to Costello syndrome patients with HRAS mutation (P = 0.04). Chaotic atrial rhythm or multifocal atrial tachycardia was observed only in Costello syndrome. Malignant tumors have been viewed as characteristic for Costello syndrome due to HRAS mutations, however, we report here on a MEK1 mutation in a patient with a malignant tumor, a hepatoblastoma. Although this indicates that the presence of a tumor is not specific for Costello syndrome with HRAS mutation, it is noteworthy that the tumor histology differs from those commonly seen in Costello syndrome. Based on these clinical differences we suggest that patients with BRAF and MEK mutations should be diagnosed with CFC syndrome, and the diagnosis of Costello syndrome be reserved for patients with HRAS mutations.",
            "authors": [
                "Gripp, KW",
                "Lin, AE",
                "Nicholson, L",
                "Allen, W",
                "Cramer, A",
                "Jones, KL",
                "Kutz, W",
                "Peck, D",
                "Rebolledo, MA",
                "Wheeler, PG",
                "Wilson, W",
                "Al-Rahawan, MM",
                "Stabley, DL",
                "Sol-Church, K"
            ],
            "is_common_article": false,
            "date_published": 20070701,
            "date_completed": 20070928,
            "format": "Article",
            "pub_med_id": 17551924,
            "title": "Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.",
            "journal": "American journal of medical genetics. Part A",
            "journal_abbreviation": "Am. J. Med. Genet. A",
            "journal_issue": "volume: 143A, issue:13"
        },
        "19603024": {
            "abstract": "BACKGROUND\nWe address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC).\n\nMETHODS\nWe determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively.\n\nRESULTS\nKRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy.\n\nCONCLUSIONS\nThese results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials.",
            "authors": [
                "Souglakos, J",
                "Philips, J",
                "Wang, R",
                "Marwah, S",
                "Silver, M",
                "Tzardi, M",
                "Silver, J",
                "Ogino, S",
                "Hooshmand, S",
                "Kwak, E",
                "Freed, E",
                "Meyerhardt, JA",
                "Saridaki, Z",
                "Georgoulias, V",
                "Finkelstein, D",
                "Fuchs, CS",
                "Kulke, MH",
                "Shivdasani, RA"
            ],
            "is_common_article": false,
            "date_published": 20090804,
            "date_completed": 20090811,
            "format": "Article",
            "pub_med_id": 19603024,
            "title": "Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer.",
            "journal": "British journal of cancer",
            "journal_abbreviation": "Br. J. Cancer",
            "journal_issue": "volume:101, issue:3"
        },
        "16372351": {
            "abstract": "Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well-characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G --> A transition in codon 12. Less frequent mutations included 35G --> C (codon 12) and 37G --> T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G --> A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G --> C had cardiac arrhythmias whereas one patient with a 37G --> T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G --> A mutation. Loss of the wild-type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio-facio-cutaneous (CFC) syndromes, the HRAS coding region was sequenced in a well-characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes.",
            "authors": [
                "Estep, AL",
                "Tidyman, WE",
                "Teitell, MA",
                "Cotter, PD",
                "Rauen, KA"
            ],
            "is_common_article": false,
            "date_published": 20060101,
            "date_completed": 20060307,
            "format": "Article",
            "pub_med_id": 16372351,
            "title": "HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.",
            "journal": "American journal of medical genetics. Part A",
            "journal_abbreviation": "Am. J. Med. Genet. A",
            "journal_issue": "volume:140, issue:1"
        },
        "15630448": {
            "abstract": "Genes crucial for cancer development can be mutated via various mechanisms, which may reflect the nature of the mutagen. In thyroid papillary carcinomas, mutations of genes coding for effectors along the MAPK pathway are central for transformation. BRAF point mutation is most common in sporadic tumors. By contrast, radiation-induced tumors are associated with paracentric inversions activating the receptor tyrosine kinases RET and NTRK1. We report here a rearrangement of BRAF via paracentric inversion of chromosome 7q resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene and exons 9-18 of BRAF. The fusion protein contains the protein kinase domain and lacks the autoinhibitory N-terminal portion of BRAF. It has elevated kinase activity and transforms NIH3T3 cells, which provides evidence, for the first time to our knowledge, of in vivo activation of an intracellular effector along the MAPK pathway by recombination. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations were absent in this group. These data indicate that in thyroid cancer, radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions, whereas in sporadic forms of the disease, effectors along the same pathway are activated predominantly by point mutations.",
            "authors": [
                "Ciampi, R",
                "Knauf, JA",
                "Kerler, R",
                "Gandhi, M",
                "Zhu, Z",
                "Nikiforova, MN",
                "Rabes, HM",
                "Fagin, JA",
                "Nikiforov, YE"
            ],
            "is_common_article": false,
            "date_published": 20050100,
            "date_completed": 20050210,
            "format": "Article",
            "pub_med_id": 15630448,
            "title": "Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer.",
            "journal": "The Journal of clinical investigation",
            "journal_abbreviation": "J. Clin. Invest.",
            "journal_issue": "volume:115, issue:1"
        },
        "20301365": {
            "abstract": "CLINICAL CHARACTERISTICS\nCardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia (ALL), has been reported in some individuals.\n\nDIAGNOSIS/TESTING\nDiagnosis is based on clinical findings and molecular genetic testing. The four genes known to be associated with CFC syndrome are: BRAF (~75%), MAP2K1 and MAP2K2 (~25%), and KRAS (<2%).\n\nMANAGEMENT\nTreatment of manifestations: Care by a multidisciplinary team; management of cardiac structural defects, hypertrophic cardiomyopathy, and arrhythmias as in the general population; increased ambient humidity or hydrating lotions for xerosis and pruritus; increased caloric intake and a nasogastric tube or gastrostomy for severe feeding problems; surgical intervention for severe gastroesophageal reflux; routine management of growth hormone deficiency, ocular abnormalities; management of seizures may require polytherapy; occupational therapy, physical therapy, and speech therapy as needed. Consensus medical management guidelines have been published. Prevention of secondary complications: Antibiotic prophylaxis for subacute bacterial endocarditis primarily for those with valve dysplasias; evaluation for hypertrophic cardiomyopathy or a predisposition to cardiac rhythm disturbances prior to anesthesia. Surveillance: Periodic echocardiogram (hypertrophic cardiomyopathy), electrocardiogram (rhythm disturbances), neurologic and eye examination, scoliosis check, and assessment of growth and cognitive development.\n\nGENETIC COUNSELING\nCardiofaciocutaneous (CFC) syndrome is inherited in an autosomal dominant manner. Most affected individuals have CFC as the result of a de novo pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting a CFC-related pathogenic variant. Prenatal testing for pregnancies at risk is possible if the BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant has been identified in an affected family member.",
            "authors": [
                "Pagon, RA",
                "Adam, MP",
                "Ardinger, HH",
                "Wallace, SE",
                "Amemiya, A",
                "Bean, LJH",
                "Bird, TD",
                "Fong, CT",
                "Mefford, HC",
                "Smith, RJH",
                "Stephens, K"
            ],
            "is_common_article": false,
            "format": "Book",
            "date_published": 19930000,
            "pub_med_id": 20301365,
            "date_completed": 20160000,
            "publisher": "University of Washington, Seattle",
            "title": "GeneReviews(®)"
        },
        "16439621": {
            "abstract": "Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, and developmental delay. We demonstrate that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer. Of the 11 mutations identified, two result in amino acid substitutions that occur in tumors, but most are unique and suggest previously unknown mechanisms of B-Raf activation. Furthermore, three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf. Our findings highlight the involvement of the MAPK pathway in human development and will provide a molecular diagnosis of CFC syndrome.",
            "authors": [
                "Rodriguez-Viciana, P",
                "Tetsu, O",
                "Tidyman, WE",
                "Estep, AL",
                "Conger, BA",
                "Cruz, MS",
                "McCormick, F",
                "Rauen, KA"
            ],
            "is_common_article": false,
            "date_published": 20060303,
            "date_completed": 20060313,
            "format": "Article",
            "pub_med_id": 16439621,
            "title": "Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.",
            "journal": "Science (New York, N.Y.)",
            "journal_abbreviation": "Science",
            "journal_issue": "volume:311, issue:5765"
        },
        "16474404": {
            "abstract": "Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.",
            "authors": [
                "Niihori, T",
                "Aoki, Y",
                "Narumi, Y",
                "Neri, G",
                "Cavé, H",
                "Verloes, A",
                "Okamoto, N",
                "Hennekam, RC",
                "Gillessen-Kaesbach, G",
                "Wieczorek, D",
                "Kavamura, MI",
                "Kurosawa, K",
                "Ohashi, H",
                "Wilson, L",
                "Heron, D",
                "Bonneau, D",
                "Corona, G",
                "Kaname, T",
                "Naritomi, K",
                "Baumann, C",
                "Matsumoto, N",
                "Kato, K",
                "Kure, S",
                "Matsubara, Y"
            ],
            "is_common_article": false,
            "date_published": 20060300,
            "date_completed": 20060502,
            "format": "Article",
            "pub_med_id": 16474404,
            "title": "Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.",
            "journal": "Nature genetics",
            "journal_abbreviation": "Nat. Genet.",
            "journal_issue": "volume:38, issue:3"
        },
        "16825433": {
            "abstract": "The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation. It is characterised by failure to thrive, relative macrocephaly, a distinctive face with prominent forehead, bitemporal constriction, absence of eyebrows, hypertelorism, downward-slanting palpebral fissures often with epicanthic folds, depressed nasal root and a bulbous tip of the nose. The cutaneous involvement consists of dry, hyperkeratotic, scaly skin, sparse and curly hair, and cavernous haemangiomata. Most patients have a congenital heart defect, most commonly pulmonic stenosis and hypertrophic cardiomyopathy. The developmental delay usually is moderate to severe. The syndrome is caused by gain-of-function mutations in four different genes BRAF, KRAS, mitogen-activated protein/extracellular signal-regulated kinase MEK1 and MEK2, all belonging to the same RAS-extracellular signal-regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis. The CFC syndrome is a member of a family of syndromes that includes the Noonan and Costello syndromes, presenting with phenotypic similarities. Noonan syndrome is caused by mutations in the protein tyrosine phosphatase SHP-2 gene (PTPN11), with a few people having a mutation in KRAS. Costello syndrome is caused by mutations in HRAS. The protein products of these genes also belong to the RAS-ERK pathway. Thus, the clinical overlap of these three conditions, which often poses a problem of differential diagnosis, is explained by their pathogenetic relatedness.",
            "authors": [
                "Roberts, A",
                "Allanson, J",
                "Jadico, SK",
                "Kavamura, MI",
                "Noonan, J",
                "Opitz, JM",
                "Young, T",
                "Neri, G"
            ],
            "is_common_article": false,
            "date_published": 20061100,
            "date_completed": 20061215,
            "format": "Article",
            "pub_med_id": 16825433,
            "title": "The cardiofaciocutaneous syndrome.",
            "journal": "Journal of medical genetics",
            "journal_abbreviation": "J. Med. Genet.",
            "journal_issue": "volume:43, issue:11"
        },
        "17483702": {
            "abstract": "Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in 2 genes that encode molecules of the RAS/MAPK (mitogen activated protein kinase) pathway (PTPN11 and HRAS, respectively). Recently, mutations in KRAS, BRAF, and MEK1/2 have been identified in patients with CFC syndrome. Somatic mutations in KRAS and BRAF have been identified in various tumors. In contrast, the association with malignancy has not been noticed in CFC syndrome. Here we report a 9-year-old boy diagnosed with CFC syndrome and acute lymphoblastic leukemia. Sequencing analysis of the entire coding region of KRAS and BRAF showed a de novo germline BRAF E501G (1502A-->G) mutation. Molecular diagnosis and careful observations should be considered in children with CFC syndrome because they have germline mutations in proto-oncogenes and might develop malignancy.",
            "authors": [
                "Makita, Y",
                "Narumi, Y",
                "Yoshida, M",
                "Niihori, T",
                "Kure, S",
                "Fujieda, K",
                "Matsubara, Y",
                "Aoki, Y"
            ],
            "is_common_article": false,
            "date_published": 20070500,
            "date_completed": 20070913,
            "format": "Article",
            "pub_med_id": 17483702,
            "title": "Leukemia in Cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene.",
            "journal": "Journal of pediatric hematology/oncology",
            "journal_abbreviation": "J. Pediatr. Hematol. Oncol.",
            "journal_issue": "volume:29, issue:5"
        },
        "23088640": {
            "abstract": "BRAF mutations have been shown to occur at a high frequency in melanoma and thyroid cancer, but also at lower frequencies in hematological malignancies. To assess the potential role of BRAF, we have sequenced exons 11 and 15 of BRAF in 138 cases with chronic lymphocytic leukemia (CLL) and 32 cases of B-cell prolymphocytic leukemia (B-PLL). We found an incidence of BRAF mutations of 2.8% in CLL (4/138), while no cases with B-PLL showed BRAF mutations. The analysis of a cohort of patients with fludarabine-refractory disease (n = 87) showed no increase in the mutation incidence, suggesting that this mutation is not selected for during the disease progression. A limited analysis of the effect of BRAF inhibition in primary CLL cells showed no cell death induction in CLL samples with and without BRAF mutations. Our analysis suggests that BRAF mutations occur at a low frequency in CLL. The pharmacological inhibition of MEK/ERK signaling using the mutant BRAF inhibitor PLX4720 showed no effect on viability in vitro in CLL cases.",
            "authors": [
                "Jebaraj, BM",
                "Kienle, D",
                "Bühler, A",
                "Winkler, D",
                "Döhner, H",
                "Stilgenbauer, S",
                "Zenz, T"
            ],
            "is_common_article": false,
            "date_published": 20130600,
            "date_completed": 20131209,
            "format": "Article",
            "pub_med_id": 23088640,
            "title": "BRAF mutations in chronic lymphocytic leukemia.",
            "journal": "Leukemia & lymphoma",
            "journal_abbreviation": "Leuk. Lymphoma",
            "journal_issue": "volume:54, issue:6"
        },
        "20523244": {
            "abstract": "Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome. Mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) have been identified in patients with CFC syndrome. BRAF mutations are involved in more than 80% of CFC syndrome patients, and we have reported earlier that 2 CFC patients with BRAF mutations developed acute lymphoblastic leukemia. Here we report a boy with CFC syndrome who developed non-Hodgkin lymphoma. At 2 months of age, he developed pneumonia with pleurisy and was diagnosed as having non-Hodgkin lymphoma (precursor T-cell lymphoblastic lymphoma) by cytopathologic examination of the pleural fluid. He was suspected of having Noonan syndrome because of his facial appearance, webbed neck, and cubitus valgus. Precursor T-cell lymphoblastic lymphoma was treated by the TCCSG NHL 94-04 protocol. At 9 years of age, he was clinically reevaluated and diagnosed as having CFC syndrome because of his distinctive facial appearance, multiple nevi, and moderate mental retardation. Sequencing analysis showed a germline p.A246P (c.736G>C) mutation in BRAF reported earlier in CFC syndrome. Molecular diagnosis and careful observation should be considered in children with CFC syndrome.",
            "authors": [
                "Ohtake, A",
                "Aoki, Y",
                "Saito, Y",
                "Niihori, T",
                "Shibuya, A",
                "Kure, S",
                "Matsubara, Y"
            ],
            "is_common_article": false,
            "date_published": 20111200,
            "date_completed": 20111220,
            "format": "Article",
            "pub_med_id": 20523244,
            "title": "Non-hodgkin lymphoma in a patient with cardiofaciocutaneous syndrome.",
            "journal": "Journal of pediatric hematology/oncology",
            "journal_abbreviation": "J. Pediatr. Hematol. Oncol.",
            "journal_issue": "volume:33, issue:8"
        },
        "21098728": {
            "abstract": "Oncogenic BRAF mutations are found in several tumor types, including melanomas and colorectal cancers. Tumors with BRAF mutations have increased mitogen-activated protein kinase pathway activity and heightened sensitivity to BRAF and MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) inhibitors. To identify potential mechanisms of acquired drug resistance, we generated clones resistant to the allosteric MEK inhibitor AZD6244 from two BRAF V600E mutant colorectal cancer cell lines that are highly sensitive to MEK or BRAF inhibition. These AZD6244-resistant (AR) clones, which exhibited cross-resistance to BRAF inhibitors, acquired resistance through amplification of the BRAF gene. A small percentage of treatment-naïve parental cells showed preexisting BRAF amplification. We observed similar amplification in a subset of cells in a BRAF-mutant colorectal cancer. In cell lines, BRAF amplification increased the abundance of phosphorylated MEK and impaired the ability of AZD6244 to inhibit ERK (extracellular signal-regulated kinase) phosphorylation. The ability of AZD6244 to inhibit ERK phosphorylation in AR cells was restored by treatment with a BRAF inhibitor at low concentrations that reduced the abundance of phosphorylated MEK to amounts observed in parental cells. Combined MEK and BRAF inhibition fully overcame resistance to MEK or BRAF inhibitors alone and was also more effective in parental cells compared to treatment with either inhibitor alone. These findings implicate BRAF amplification as a mechanism of resistance to both MEK and BRAF inhibitors and suggest combined MEK and BRAF inhibition as a clinical strategy to overcome, or possibly prevent, this mechanism of resistance.",
            "authors": [
                "Corcoran, RB",
                "Dias-Santagata, D",
                "Bergethon, K",
                "Iafrate, AJ",
                "Settleman, J",
                "Engelman, JA"
            ],
            "is_common_article": false,
            "date_published": 20101123,
            "date_completed": 20110302,
            "format": "Article",
            "pub_med_id": 21098728,
            "title": "BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation.",
            "journal": "Science signaling",
            "journal_abbreviation": "Sci Signal",
            "journal_issue": "volume:3, issue:149"
        },
        "21349766": {
            "abstract": "Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11, rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease.",
            "authors": [
                "Romano, E",
                "Schwartz, GK",
                "Chapman, PB",
                "Wolchock, JD",
                "Carvajal, RD"
            ],
            "is_common_article": false,
            "date_published": 20110900,
            "date_completed": 20111024,
            "format": "Article",
            "pub_med_id": 21349766,
            "title": "Treatment implications of the emerging molecular classification system for melanoma.",
            "journal": "The Lancet. Oncology",
            "journal_abbreviation": "Lancet Oncol.",
            "journal_issue": "volume:12, issue:9"
        },
        "26732095": {
            "abstract": "UNLABELLED\nWe have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the β3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490-deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer-dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive.\n\nSIGNIFICANCE\nThis study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer.",
            "authors": [
                "Chen, SH",
                "Zhang, Y",
                "Van Horn, RD",
                "Yin, T",
                "Buchanan, S",
                "Yadav, V",
                "Mochalkin, I",
                "Wong, SS",
                "Yue, YG",
                "Huber, L",
                "Conti, I",
                "Henry, JR",
                "Starling, JJ",
                "Plowman, GD",
                "Peng, SB"
            ],
            "is_common_article": false,
            "date_published": 20160300,
            "date_completed": 20161213,
            "format": "Article",
            "pub_med_id": 26732095,
            "title": "Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120.",
            "journal": "Cancer discovery",
            "journal_abbreviation": "Cancer Discov",
            "journal_issue": "volume:6, issue:3"
        },
        "21396583": {
            "abstract": "Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations.",
            "authors": [
                "Tartaglia, M",
                "Gelb, BD",
                "Zenker, M"
            ],
            "is_common_article": false,
            "date_published": 20110200,
            "date_completed": 20110705,
            "format": "Article",
            "pub_med_id": 21396583,
            "title": "Noonan syndrome and clinically related disorders.",
            "journal": "Best practice & research. Clinical endocrinology & metabolism",
            "journal_abbreviation": "Best Pract. Res. Clin. Endocrinol. Metab.",
            "journal_issue": "volume:25, issue:1"
        },
        "24112392": {
            "abstract": "AIM\nColorectal cancer is a heterogeneous disease with multiple underlying genetic mutations resulting in different phenotypes. Mutation in the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) proto-oncogene is an important event in the methylator pathway. There is no consensus, however, on the clinicopathological characteristics associated with BRAF mutation.\n\nMETHOD\nA comprehensive search for published studies examining the effect of BRAF mutation on colorectal cancer was performed. Random effects methods were used to combine data.\n\nRESULTS\nData were retrieved from 21 studies describing 9885 patients. BRAF associated colorectal cancer is associated with proximal tumour location (OR 5.222, 95% CI 3.801-7.174, P < 0.001), T4 tumours (OR 1.761, 95% CI 1.164-2.663, P = 0.007) and poor differentiation (OR 3.816, 95% CI 2.714-5.365, P < 0.001) and is negatively associated with male sex (OR 0.623, 95% CI 0.505-0.769, P < 0.001), age of diagnosis under 60 years (OR 0.453, 95% CI 0.280-0.733, P = 0.001) and rectal cancer (OR 0.266, 95% CI 0.122-0.422, P < 0.001).\n\nCONCLUSION\nBRAF mutation appears to be associated with distinct, unfavourable clinicopathological characteristics in colorectal cancer.",
            "authors": [
                "Clancy, C",
                "Burke, JP",
                "Kalady, MF",
                "Coffey, JC"
            ],
            "is_common_article": false,
            "date_published": 20131200,
            "date_completed": 20140718,
            "format": "Article",
            "pub_med_id": 24112392,
            "title": "BRAF mutation is associated with distinct clinicopathological characteristics in colorectal cancer: a systematic review and meta-analysis.",
            "journal": "Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland",
            "journal_abbreviation": "Colorectal Dis",
            "journal_issue": "volume:15, issue:12"
        },
        "21495173": {
            "abstract": "Cardio-facio-cutaneous (CFC) syndrome is a sporadic multiple congenital anomalies/mental retardation condition principally caused by mutations in BRAF, MEK1, and MEK2. Mutations in KRAS and SHOC2 lead to a phenotype with overlapping features. In approximately 10–30% of individuals with a clinical diagnosis of CFC, a mutation in one of these causative genes is not found. Cardinal features of CFC include congenital heart defects, a characteristic facial appearance, and ectodermal abnormalities. Additional features include failure to thrive with severe feeding problems, moderate to severe intellectual disability and short stature with relative macrocephaly. First described in 1986, more than 100 affected individuals are reported. Following the discovery of the causative genes, more information has emerged on the breadth of clinical features. Little, however, has been published on genotype–phenotype correlations. This clinical study of 186 children and young adults with mutation-proven CFC syndrome is the largest reported to date. BRAF mutations are documented in 140 individuals (approximately 75%), while 46 (approximately 25%) have a mutation in MEK 1 or MEK 2. The age range is 6 months to 32 years, the oldest individual being a female from the original report [Reynolds et al. (1986); Am J Med Genet 25:413–427]. While some clinical data on 136 are in the literature, 50 are not previously published. We provide new details of the breadth of phenotype and discuss the frequency of particular features in each genotypic group. Pulmonary stenosis is the only anomaly that demonstrates a statistically significant genotype–phenotype correlation, being more common in individuals with a BRAF mutation.",
            "authors": [
                "Allanson, JE",
                "Annerén, G",
                "Aoki, Y",
                "Armour, CM",
                "Bondeson, ML",
                "Cave, H",
                "Gripp, KW",
                "Kerr, B",
                "Nystrom, AM",
                "Sol-Church, K",
                "Verloes, A",
                "Zenker, M"
            ],
            "is_common_article": false,
            "date_published": 20110515,
            "date_completed": 20110809,
            "format": "Article",
            "pub_med_id": 21495173,
            "title": "Cardio-facio-cutaneous syndrome: does genotype predict phenotype?",
            "journal": "American journal of medical genetics. Part C, Seminars in medical genetics",
            "journal_abbreviation": "Am J Med Genet C Semin Med Genet",
            "journal_issue": "volume: 157C, issue:2"
        },
        "21641636": {
            "abstract": "BACKGROUND\nIn the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.\n\nMETHODS\nIn this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.\n\nFINDINGS\n1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3-29·2] in the control group vs 17·0 months [9·4-30·1] in the cetuximab group; HR 1·04, 95% CI 0·87-1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0-12·5] in the control group vs 8·6 months [5·1-13·8] in the cetuximab group; HR 0·96, 0·82-1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5-27·4); KRAS mutant, 14·4 months (8·5-24·0); all wild-type, 20·1 months (11·5-31·7).\n\nINTERPRETATION\nThis trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.\n\nFUNDING\nCancer Research UK, Cancer Research Wales, UK Medical Research Council, Merck KGgA.",
            "authors": [
                "Maughan, TS",
                "Adams, RA",
                "Smith, CG",
                "Meade, AM",
                "Seymour, MT",
                "Wilson, RH",
                "Idziaszczyk, S",
                "Harris, R",
                "Fisher, D",
                "Kenny, SL",
                "Kay, E",
                "Mitchell, JK",
                "Madi, A",
                "Jasani, B",
                "James, MD",
                "Bridgewater, J",
                "Kennedy, MJ",
                "Claes, B",
                "Lambrechts, D",
                "Kaplan, R",
                "Cheadle, JP"
            ],
            "is_common_article": false,
            "date_published": 20110618,
            "date_completed": 20110628,
            "format": "Article",
            "pub_med_id": 21641636,
            "title": "Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.",
            "journal": "Lancet (London, England)",
            "journal_abbreviation": "Lancet",
            "journal_issue": "volume:377, issue:9783"
        },
        "22169769": {
            "abstract": "The MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity. Among RAF/RAS mutant lines, co-occurring PIK3CA/PTEN mutations conferred a cytostatic response instead of a cytotoxic response for colon cancer cells that have the biggest representation of the comutations. Among KRAS mutant cell lines, transcriptomics analysis showed that cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition were less sensitive to GSK1120212. In addition, a proportion of cell lines from certain tissue types not known to carry frequent RAF/RAS mutations also seemed to be sensitive to GSK1120212. Among these were breast cancer cell lines, with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes. We identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212 and lack of expression associated with resistance irrelevant of RAF/RAS status. Among hematologic cell lines, acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive. Overall, this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF/RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF/RAS wild-type status of their tumors.",
            "authors": [
                "Jing, J",
                "Greshock, J",
                "Holbrook, JD",
                "Gilmartin, A",
                "Zhang, X",
                "McNeil, E",
                "Conway, T",
                "Moy, C",
                "Laquerre, S",
                "Bachman, K",
                "Wooster, R",
                "Degenhardt, Y"
            ],
            "is_common_article": false,
            "date_published": 20120300,
            "date_completed": 20120709,
            "format": "Article",
            "pub_med_id": 22169769,
            "title": "Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212.",
            "journal": "Molecular cancer therapeutics",
            "journal_abbreviation": "Mol. Cancer Ther.",
            "journal_issue": "volume:11, issue:3"
        },
        "19047498": {
            "authors": [
                "Neri, G",
                "Allanson, J",
                "Kavamura, MI"
            ],
            "is_common_article": false,
            "date_published": 20081200,
            "date_completed": 20090202,
            "format": "Article",
            "pub_med_id": 19047498,
            "title": "No reason yet to change diagnostic criteria for Noonan, Costello and cardio-facio-cutaneous syndromes.",
            "journal": "Journal of medical genetics",
            "journal_abbreviation": "J. Med. Genet.",
            "journal_issue": "volume:45, issue:12"
        },
        "22639828": {
            "authors": [
                "Ping, N",
                "Wang, Q",
                "Wang, Q",
                "Dong, S",
                "Wu, L",
                "Xue, Y",
                "Ruan, C",
                "Wu, D",
                "Chen, S"
            ],
            "is_common_article": false,
            "date_published": 20121200,
            "date_completed": 20130415,
            "format": "Article",
            "pub_med_id": 22639828,
            "title": "Absence of BRAF V600E mutation in hematologic malignancies excluding hairy-cell leukemia.",
            "journal": "Leukemia & lymphoma",
            "journal_abbreviation": "Leuk. Lymphoma",
            "journal_issue": "volume:53, issue:12"
        },
        "22946697": {
            "abstract": "Cardio-facio-cutaneous syndrome (CFC) is a RASopathy that is characterized by craniofacial, dermatologic, gastrointestinal, ocular, cardiac, and neurologic anomalies. CFC is caused by activating mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathway that is downstream of receptor tyrosine kinase (RTK) signaling. RTK signaling is known to play a central role in craniofacial and dental development, but to date, no studies have systematically examined individuals with CFC to define key craniofacial and dental features. To fill this critical gap in our knowledge, we evaluated the craniofacial and dental phenotype of a large cohort (n = 32) of CFC individuals who attended the 2009 and 2011 CFC International Family Conferences. We quantified common craniofacial features in CFC which include macrocephaly, bitemporal narrowing, convex facial profile, and hypoplastic supraorbital ridges. In addition, there is a characteristic dental phenotype in CFC syndrome that includes malocclusion with open bite, posterior crossbite, and a high-arched palate. This thorough evaluation of the craniofacial and dental phenotype in CFC individuals provides a step forward in our understanding of the role of RTK/MAPK signaling in human craniofacial development and will aid clinicians who treat patients with CFC.",
            "authors": [
                "Goodwin, AF",
                "Oberoi, S",
                "Landan, M",
                "Charles, C",
                "Groth, J",
                "Martinez, A",
                "Fairley, C",
                "Weiss, LA",
                "Tidyman, WE",
                "Klein, OD",
                "Rauen, KA"
            ],
            "is_common_article": false,
            "date_published": 20130600,
            "date_completed": 20131204,
            "format": "Article",
            "pub_med_id": 22946697,
            "title": "Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis.",
            "journal": "Clinical genetics",
            "journal_abbreviation": "Clin. Genet.",
            "journal_issue": "volume:83, issue:6"
        },
        "23817572": {
            "abstract": "Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.",
            "authors": [
                "Jones, DT",
                "Hutter, B",
                "Jäger, N",
                "Korshunov, A",
                "Kool, M",
                "Warnatz, HJ",
                "Zichner, T",
                "Lambert, SR",
                "Ryzhova, M",
                "Quang, DA",
                "Fontebasso, AM",
                "Stütz, AM",
                "Hutter, S",
                "Zuckermann, M",
                "Sturm, D",
                "Gronych, J",
                "Lasitschka, B",
                "Schmidt, S",
                "Seker-Cin, H",
                "Witt, H",
                "Sultan, M",
                "Ralser, M",
                "Northcott, PA",
                "Hovestadt, V",
                "Bender, S",
                "Pfaff, E",
                "Stark, S",
                "Faury, D",
                "Schwartzentruber, J",
                "Majewski, J",
                "Weber, UD",
                "Zapatka, M",
                "Raeder, B",
                "Schlesner, M",
                "Worth, CL",
                "Bartholomae, CC",
                "von Kalle, C",
                "Imbusch, CD",
                "Radomski, S",
                "Lawerenz, C",
                "van Sluis, P",
                "Koster, J",
                "Volckmann, R",
                "Versteeg, R",
                "Lehrach, H",
                "Monoranu, C",
                "Winkler, B",
                "Unterberg, A",
                "Herold-Mende, C",
                "Milde, T",
                "Kulozik, AE",
                "Ebinger, M",
                "Schuhmann, MU",
                "Cho, YJ",
                "Pomeroy, SL",
                "von Deimling, A",
                "Witt, O",
                "Taylor, MD",
                "Wolf, S",
                "Karajannis, MA",
                "Eberhart, CG",
                "Scheurlen, W",
                "Hasselblatt, M",
                "Ligon, KL",
                "Kieran, MW",
                "Korbel, JO",
                "Yaspo, ML",
                "Brors, B",
                "Felsberg, J",
                "Reifenberger, G",
                "Collins, VP",
                "Jabado, N",
                "Eils, R",
                "Lichter, P",
                "Pfister, SM"
            ],
            "is_common_article": false,
            "date_published": 20130800,
            "date_completed": 20131017,
            "format": "Article",
            "pub_med_id": 23817572,
            "title": "Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.",
            "journal": "Nature genetics",
            "journal_abbreviation": "Nat. Genet.",
            "journal_issue": "volume:45, issue:8"
        },
        "23875798": {
            "abstract": "The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration.",
            "authors": [
                "Rauen, KA"
            ],
            "is_common_article": false,
            "date_published": 20130000,
            "date_completed": 20131202,
            "format": "Article",
            "pub_med_id": 23875798,
            "title": "The RASopathies.",
            "journal": "Annual review of genomics and human genetics",
            "journal_abbreviation": "Annu Rev Genomics Hum Genet",
            "journal_issue": "volume:14"
        },
        "23890088": {
            "abstract": "BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers, BRAF is activated by rearrangements that fuse its kinase domain to 5' partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six N-terminal partners. No other mutations were identified in melanoma oncogenes. One of the seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP kinase pathway. Sorafenib, but not vemurafenib, could block MAP kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAF(V) (600E) mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib.",
            "authors": [
                "Botton, T",
                "Yeh, I",
                "Nelson, T",
                "Vemula, SS",
                "Sparatta, A",
                "Garrido, MC",
                "Allegra, M",
                "Rocchi, S",
                "Bahadoran, P",
                "McCalmont, TH",
                "LeBoit, PE",
                "Burton, EA",
                "Bollag, G",
                "Ballotti, R",
                "Bastian, BC"
            ],
            "is_common_article": false,
            "date_published": 20131100,
            "date_completed": 20140527,
            "format": "Article",
            "pub_med_id": 23890088,
            "title": "Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy.",
            "journal": "Pigment cell & melanoma research",
            "journal_abbreviation": "Pigment Cell Melanoma Res",
            "journal_issue": "volume:26, issue:6"
        },
        "24345920": {
            "abstract": "PURPOSE\nRecurrent \"driver\" mutations at specific loci in BRAF, NRAS, KIT, GNAQ, and GNA11 define clinically relevant molecular subsets of melanoma, but more than 30% are \"pan-negative\" for these recurrent mutations. We sought to identify additional potential drivers in \"pan-negative\" melanoma.\n\nEXPERIMENTAL DESIGN\nUsing a targeted next-generation sequencing (NGS) assay (FoundationOne™) and targeted RNA sequencing, we identified a novel PAPSS1-BRAF fusion in a \"pan-negative\" melanoma. We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOne™, as well as melanoma RNA, whole-genome and whole-exome sequencing data in The Cancer Genome Atlas (TCGA), to determine the potential frequency of BRAF fusions in melanoma. We characterized the signaling properties of confirmed molecular alterations by ectopic expression of engineered cDNAs in 293H cells.\n\nRESULTS\nActivation of the mitogen-activated protein kinase (MAPK) pathway in cells by ectopic expression of PAPSS1-BRAF was abrogated by mitogen-activated protein kinase kinase (MEK) inhibition but not by BRAF inhibition. NGS data analysis of 51 additional melanomas revealed a second BRAF fusion (TRIM24-BRAF) in a \"pan-negative\" sample; MAPK signaling induced by TRIM24-BRAF was also MEK inhibitor sensitive. Through mining TCGA skin cutaneous melanoma dataset, we further identified two potential BRAF fusions in another 49 \"pan-negative\" cases.\n\nCONCLUSIONS\nBRAF fusions define a new molecular subset of melanoma, potentially comprising 4% to 8% of \"pan-negative\" cases. Their presence may explain an unexpected clinical response to MEK inhibitor therapy or assist in selecting patients for MEK-directed therapy.",
            "authors": [
                "Hutchinson, KE",
                "Lipson, D",
                "Stephens, PJ",
                "Otto, G",
                "Lehmann, BD",
                "Lyle, PL",
                "Vnencak-Jones, CL",
                "Ross, JS",
                "Pietenpol, JA",
                "Sosman, JA",
                "Puzanov, I",
                "Miller, VA",
                "Pao, W"
            ],
            "is_common_article": false,
            "date_published": 20131215,
            "date_completed": 20140826,
            "format": "Article",
            "pub_med_id": 24345920,
            "title": "BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition.",
            "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
            "journal_abbreviation": "Clin. Cancer Res.",
            "journal_issue": "volume:19, issue:24"
        },
        "24422672": {
            "abstract": "BACKGROUND\nOncologic patients who are extreme responders to molecularly targeted therapy provide an important opportunity to better understand the biologic basis of response and, in turn, inform clinical decision making. Malignant neoplasms with an uncertain histologic and immunohistochemical characterization present challenges both on initial diagnostic workups and then later in management, as current treatment algorithms are based on a morphologic diagnosis. Herein, we report a case of a difficult to characterize sarcoma-like lesion for which genomic profiling with clinical next generation sequencing (NGS) identified the molecular underpinnings of arrested progression(stable disease) under combination targeted therapy within a phase I clinical trial.\n\nMETHODS\nGenomic profiling with clinical next generation sequencing was performed on the FoundationOne™ platform (Foundation Medicine, Cambridge MA). Histopathology and immunohistochemical studies were performed in the Department of Pathology, MD Anderson Cancer Center (Houston, TX). Treatment was administered in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01187199).\n\nRESULTS\nThe histology of the tumor was that of a spindle cell neoplasm, grade 2 by FNCLCC standards. Immunohistochemical staining was positive for S100 and CD34. Genomic profiling identified the following alterations: a KIAA1549-BRAF gene fusion resulting from a tandem duplication event, a homozygous deletion of PTEN, and frameshift insertion/deletions in CDKN2A A68fs*51, SUFU E283fs*3, and MAP3K1 N325fs*3. The patient had a 25% reduction in tumor (RECIST v1.1) following combination therapy consisting of sorafenib, temsirolimus, and bevazicumab within a phase I clinical trial.\n\nCONCLUSIONS\nThe patient responded to combination targeted therapy that fortuitously targeted KIAA1549-BRAF and PTEN loss within a spindle cell neoplasm, as revealed by genomic profiling based on NGS. This is the first report of a tumor driven by a KIAA1549-BRAF fusion responding to sorafenib-based combination therapy.",
            "authors": [
                "Subbiah, V",
                "Westin, SN",
                "Wang, K",
                "Araujo, D",
                "Wang, WL",
                "Miller, VA",
                "Ross, JS",
                "Stephens, PJ",
                "Palmer, GA",
                "Ali, SM"
            ],
            "is_common_article": false,
            "date_published": 20140114,
            "date_completed": 20140926,
            "format": "Article",
            "pub_med_id": 24422672,
            "title": "Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein.",
            "journal": "Journal of hematology & oncology",
            "journal_abbreviation": "J Hematol Oncol",
            "journal_issue": "volume:7"
        },
        "22586653": {
            "abstract": "UNLABELLED\nOnly a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples (\"xenopatients\") to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2-amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal cancer, whose medical treatment in the chemorefractory setting remains an unmet clinical need.\n\nSIGNIFICANCE\nDirect transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, combining the flexibility of preclinical analysis with the informative value of population-based studies. Our suite of patient-derived xenografts from metastatic colorectal carcinomas reliably mimicked disease response in humans, prospectively recapitulated biomarker-based case stratification, and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting.",
            "authors": [
                "Bertotti, A",
                "Migliardi, G",
                "Galimi, F",
                "Sassi, F",
                "Torti, D",
                "Isella, C",
                "Corà, D",
                "Di Nicolantonio, F",
                "Buscarino, M",
                "Petti, C",
                "Ribero, D",
                "Russolillo, N",
                "Muratore, A",
                "Massucco, P",
                "Pisacane, A",
                "Molinaro, L",
                "Valtorta, E",
                "Sartore-Bianchi, A",
                "Risio, M",
                "Capussotti, L",
                "Gambacorta, M",
                "Siena, S",
                "Medico, E",
                "Sapino, A",
                "Marsoni, S",
                "Comoglio, PM",
                "Bardelli, A",
                "Trusolino, L"
            ],
            "is_common_article": false,
            "date_published": 20111100,
            "date_completed": 20121121,
            "format": "Article",
            "pub_med_id": 22586653,
            "title": "A molecularly annotated platform of patient-derived xenografts (\"xenopatients\") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer.",
            "journal": "Cancer discovery",
            "journal_abbreviation": "Cancer Discov",
            "journal_issue": "volume:1, issue:6"
        },
        "24428489": {
            "authors": [
                "Samuel, J",
                "Macip, S",
                "Dyer, MJ"
            ],
            "is_common_article": false,
            "date_published": 20140116,
            "date_completed": 20140204,
            "format": "Article",
            "pub_med_id": 24428489,
            "title": "Efficacy of vemurafenib in hairy-cell leukemia.",
            "journal": "The New England journal of medicine",
            "journal_abbreviation": "N. Engl. J. Med.",
            "journal_issue": "volume:370, issue:3"
        }
    },
    "identifiers": {
        "hgnc_previous_symbol": null,
        "hgnc_id": null,
        "uniprot_id": [
            "H7C4S5",
            "H7C560",
            "H7C5K3",
            "P15056"
        ],
        "ensembl_id": null,
        "entrez_id": [
            "673"
        ],
        "lrg_id": [
            "LRG_299"
        ]
    },
    "ghr_genes": {
        "version": "06_nov_2019",
        "items": [
            {
                "html_text": "

The BRAF gene provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell's nucleus. This protein is part of a signaling pathway known as the RAS/MAPK pathway, which controls several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth.

The BRAF gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.

", "date_published_by_ghr": "2019-10-29", "conditions_list": [ { "name": "Cardiofaciocutaneous Syndrome", "html_text": "

Cardiofaciocutaneous syndrome is a disorder that affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (cutaneous). People with this condition also have delayed development and intellectual disability, usually ranging from moderate to severe.

Heart defects occur in most people with cardiofaciocutaneous syndrome. The heart problems most commonly associated with this condition include malformations of one of the heart valves that impairs blood flow from the heart to the lungs (pulmonic stenosis), a hole between the two upper chambers of the heart (atrial septal defect), and a form of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy).

Cardiofaciocutaneous syndrome is also characterized by distinctive facial features. These include a high forehead that narrows at the temples, a short nose, widely spaced eyes (ocular hypertelorism), outside corners of the eyes that point downward (down-slanting palpebral fissures), droopy eyelids (ptosis), a small chin, and low-set ears. Overall, the face is broad and long, and the facial features are sometimes described as \"coarse.\"

Skin abnormalities occur in almost everyone with cardiofaciocutaneous syndrome. Many affected people have dry, rough skin; dark-colored moles (nevi); wrinkled palms and soles; and a skin condition called keratosis pilaris, which causes small bumps to form on the arms, legs, and face. People with cardiofaciocutaneous syndrome also tend to have thin, dry, curly hair and sparse or absent eyelashes and eyebrows.

Infants with cardiofaciocutaneous syndrome typically have weak muscle tone (hypotonia), feeding difficulties, and a failure to grow and gain weight at the normal rate (failure to thrive). Additional features of this disorder in children and adults can include an unusually large head (macrocephaly), short stature, problems with vision, and seizures.

The signs and symptoms of cardiofaciocutaneous syndrome overlap significantly with those of two other genetic conditions, Costello syndrome and Noonan syndrome. The three conditions are distinguished by their genetic cause and specific patterns of signs and symptoms; however, it can be difficult to tell these conditions apart, particularly in infancy. Unlike Costello syndrome, which significantly increases a person's cancer risk, cancer does not appear to be a major feature of cardiofaciocutaneous syndrome.

", "ghr_link": "https://ghr.nlm.nih.gov/condition/cardiofaciocutaneous-syndrome" }, { "name": "Cholangiocarcinoma", "html_text": "

Cholangiocarcinoma is a group of cancers that begin in the bile ducts. Bile ducts are branched tubes that connect the liver and gallbladder to the small intestine. They carry bile, which is a fluid that helps the body digest the fats in food. Bile is produced in the liver and stored in the gallbladder before being released in the small intestine after a person eats.

Cholangiocarcinoma is classified by its location in relation to the liver. Intrahepatic cholangiocarcinoma begins in the small bile ducts within the liver. This is the least common form of the disease, accounting for less than 10 percent of all cases. Perihilar cholangiocarcinoma (also known as a Klatskin tumor) begins in an area called the hilum, where two major bile ducts join and leave the liver. It is the most common form of the disease, accounting for more than half of all cases. The remaining cases are classified as distal cholangiocarcinomas, which begin in bile ducts outside the liver. The perihilar and distal forms of the disease, which both occur outside the liver, are sometimes grouped together and called extrahepatic cholangiocarcinoma.

The three types of cholangiocarcinoma do not usually cause any symptoms in their early stages, and this cancer is usually not diagnosed until it has already spread beyond the bile ducts to other tissues. Symptoms often result when bile ducts become blocked by the tumor. The most common symptom is jaundice, which is a yellowing of the skin and the whites of the eyes. Other symptoms can include itching, dark-colored urine, loss of appetite, unintentional weight loss, abdominal pain, and light-colored and greasy stools. These symptoms are described as \"nonspecific\" because they can be features of many different diseases.

Most people who develop cholangiocarcinoma are older than 65. Because this cancer is often not discovered until it has already spread, it can be challenging to treat effectively. Affected individuals can survive for several months to several years after diagnosis.

", "ghr_link": "https://ghr.nlm.nih.gov/condition/cholangiocarcinoma" }, { "name": "Erdheim-Chester Disease", "html_text": "

Erdheim-Chester disease is a rare type of slow-growing blood cancer called a histiocytic neoplasm, which results in overproduction of cells called histiocytes. Histiocytes normally function to destroy foreign substances and protect the body from infection. In Erdheim-Chester disease, the excess production of histiocytes (histiocytosis) leads to inflammation that can damage organs and tissues throughout the body, causing them to become thickened, dense, and scarred (fibrotic); this tissue damage may lead to organ failure.

People with Erdheim-Chester disease often have bone pain, especially in the lower legs and upper arms, due to an abnormal increase in bone density (osteosclerosis). Damage to the pituitary gland (a structure at the base of the brain that produces several hormones, including a hormone that controls the amount of water released in the urine) may result in hormonal problems such as a condition called diabetes insipidus that leads to excessive urination. Abnormally high pressure of the cerebrospinal fluid within the skull (intracranial hypertension) caused by accumulation of histiocytes in the brain may result in headaches, seizures, cognitive impairment, or problems with movement or sensation. People with this condition can also have shortness of breath, heart or kidney disease, protruding eyes (exophthalmos), skin growths, or inability to conceive a child (infertility). Affected individuals may also experience fever, night sweats, fatigue, weakness, and weight loss.

The signs and symptoms of Erdheim-Chester disease usually appear between the ages of 40 and 60, although the disorder can occur at any age. The severity of the condition varies widely; some affected individuals have few or no associated health problems, while others have severe complications that can be life-threatening.

", "ghr_link": "https://ghr.nlm.nih.gov/condition/erdheim-chester-disease" }, { "name": "Gastrointestinal Stromal Tumor", "html_text": "

A gastrointestinal stromal tumor (GIST) is a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine. The tumors are thought to grow from specialized cells found in the gastrointestinal tract called interstitial cells of Cajal (ICCs) or precursors to these cells. GISTs are usually found in adults between ages 40 and 70; rarely, children and young adults develop these tumors. The tumors can be cancerous (malignant) or noncancerous (benign).

Small tumors may cause no signs or symptoms. However, some people with GISTs may experience pain or swelling in the abdomen, nausea, vomiting, loss of appetite, or weight loss. Sometimes, tumors cause bleeding, which may lead to low red blood cell counts (anemia) and, consequently, weakness and tiredness. Bleeding into the intestinal tract may cause black and tarry stools, and bleeding into the throat or stomach may cause vomiting of blood.

Affected individuals with no family history of GIST typically have only one tumor (called a sporadic GIST). People with a family history of GISTs (called familial GISTs) often have multiple tumors and additional signs or symptoms, including noncancerous overgrowth (hyperplasia) of other cells in the gastrointestinal tract and patches of dark skin on various areas of the body. Some affected individuals have a skin condition called urticaria pigmentosa (also known as cutaneous mastocytosis), which is characterized by raised patches of brownish skin that sting or itch when touched.

", "ghr_link": "https://ghr.nlm.nih.gov/condition/gastrointestinal-stromal-tumor" }, { "name": "Giant Congenital Melanocytic Nevus", "html_text": "

Giant congenital melanocytic nevus is a skin condition characterized by an abnormally dark, noncancerous skin patch (nevus) that is composed of pigment-producing cells called melanocytes. It is present from birth (congenital) or is noticeable soon after birth. The nevus may be small in infants, but it will usually grow at the same rate the body grows and will eventually be at least 40 cm (15.75 inches) across. The nevus can appear anywhere on the body, but it is more often found on the trunk or limbs. The color ranges from tan to black and can become darker or lighter over time. The surface of a nevus can be flat, rough, raised, thickened, or bumpy; the surface can vary in different regions of the nevus, and it can change over time. The skin of the nevus is often dry and prone to irritation and itching (dermatitis). Excessive hair growth (hypertrichosis) can occur within the nevus. There is often less fat tissue under the skin of the nevus; the skin may appear thinner there than over other areas of the body.

People with giant congenital melanocytic nevus may have more than one nevus (plural: nevi). The other nevi are often smaller than the giant nevus. Affected individuals may have one or two additional nevi or multiple small nevi that are scattered over the skin; these are known as satellite or disseminated nevi.

Affected individuals may feel anxiety or emotional stress due to the impact the nevus may have on their appearance and their health. Children with giant congenital melanocytic nevus can develop emotional or behavior problems.

Some people with giant congenital melanocytic nevus develop a condition called neurocutaneous melanosis, which is the presence of pigment-producing skin cells (melanocytes) in the tissue that covers the brain and spinal cord. These melanocytes may be spread out or grouped together in clusters. Their growth can cause increased pressure in the brain, leading to headache, vomiting, irritability, seizures, and movement problems. Tumors in the brain may also develop.

Individuals with giant congenital melanocytic nevus have an increased risk of developing an aggressive form of skin cancer called melanoma, which arises from melanocytes. Estimates vary, but it is generally thought that people with giant congenital melanocytic nevus have a 5 to 10 percent lifetime risk of developing melanoma. Melanoma commonly begins in the nevus, but it can develop when melanocytes that invade other tissues, such as those in the brain and spinal cord, become cancerous. When melanoma occurs in people with giant congenital melanocytic nevus, the survival rate is low.

Other types of tumors can also develop in individuals with giant congenital melanocytic nevus, including soft tissue tumors (sarcomas), fatty tumors (lipomas), and tumors of the nerve cells (schwannomas).

", "ghr_link": "https://ghr.nlm.nih.gov/condition/giant-congenital-melanocytic-nevus" }, { "name": "Langerhans Cell Histiocytosis", "html_text": "

Langerhans cell histiocytosis is a disorder in which excess immune system cells called Langerhans cells build up in the body. Langerhans cells, which help regulate the immune system, are normally found throughout the body, especially in the skin, lymph nodes, spleen, lungs, liver, and bone marrow. In Langerhans cell histiocytosis, excess immature Langerhans cells usually form tumors called granulomas. Many researchers now consider Langerhans cell histiocytosis to be a form of cancer, but this classification remains controversial.

In approximately 80 percent of affected individuals, one or more granulomas develop in the bones, causing pain and swelling. The granulomas, which usually occur in the skull or the long bones of the arms or legs, may cause the bone to fracture.

Granulomas also frequently occur in the skin, appearing as blisters, reddish bumps, or rashes which can be mild to severe. The pituitary gland may also be affected; this gland is located at the base of the brain and produces hormones that control many important body functions. Without hormone supplementation, affected individuals may experience delayed or absent puberty or an inability to have children (infertility). In addition, pituitary gland damage may result in the production of excessive amounts of urine (diabetes insipidus) and dysfunction of another gland called the thyroid. Thyroid dysfunction can affect the rate of chemical reactions in the body (metabolism), body temperature, skin and hair texture, and behavior.

In 15 to 20 percent of cases, Langerhans cell histiocytosis affects the lungs, liver, or blood-forming (hematopoietic) system; damage to these organs and tissues may be life-threatening. Lung involvement, which appears as swelling of the small airways (bronchioles) and blood vessels of the lungs, results in stiffening of the lung tissue, breathing problems, and increased risk of infection. Hematopoietic involvement, which occurs when the Langerhans cells crowd out blood-forming cells in the bone marrow, leads to a general reduction in the number of blood cells (pancytopenia). Pancytopenia results in fatigue due to low numbers of red blood cells (anemia), frequent infections due to low numbers of white blood cells (neutropenia), and clotting problems due to low numbers of platelets (thrombocytopenia).

Other signs and symptoms that may occur in Langerhans cell histiocytosis, depending on which organs and tissues have Langerhans cell deposits, include swollen lymph nodes, abdominal pain, yellowing of the skin and whites of the eyes (jaundice), delayed puberty, protruding eyes, dizziness, irritability, and seizures. About 1 in 50 affected individuals experience deterioration of neurological function (neurodegeneration).

Langerhans cell histiocytosis is often diagnosed in childhood, usually between ages 2 and 3, but can appear at any age. Most individuals with adult-onset Langerhans cell histiocytosis are current or past smokers; in about two-thirds of adult-onset cases the disorder affects only the lungs.

The severity of Langerhans cell histiocytosis, and its signs and symptoms, vary widely among affected individuals. Certain presentations or forms of the disorder were formerly considered to be separate diseases. Older names that were sometimes used for forms of Langerhans cell histiocytosis include eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease.

In many people with Langerhans cell histiocytosis, the disorder eventually goes away with appropriate treatment. It may even disappear on its own, especially if the disease occurs only in the skin. However, some complications of the condition, such as diabetes insipidus or other effects of tissue and organ damage, may be permanent.

", "ghr_link": "https://ghr.nlm.nih.gov/condition/langerhans-cell-histiocytosis" }, { "name": "Lung Cancer", "html_text": "

Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Lung cancer may not cause signs or symptoms in its early stages. Some people with lung cancer have chest pain, frequent coughing, blood in the mucus, breathing problems, trouble swallowing or speaking, loss of appetite and weight loss, fatigue, or swelling in the face or neck. Additional symptoms can develop if the cancer spreads (metastasizes) into other tissues. Lung cancer occurs most often in adults in their sixties or seventies. Most people who develop lung cancer have a history of long-term tobacco smoking; however, the condition can occur in people who have never smoked.

Lung cancer is generally divided into two types, small cell lung cancer and non-small cell lung cancer, based on the size of the affected cells when viewed under a microscope. Non-small cell lung cancer accounts for 85 percent of lung cancer, while small cell lung cancer accounts for the remaining 15 percent.

Small cell lung cancer grows quickly and in more than half of cases the cancer has spread beyond the lung by the time the condition is diagnosed. Small cell lung cancer often metastasizes, most commonly to the liver, brain, bones, and adrenal glands (small hormone-producing glands located on top of each kidney). After diagnosis, most people with small cell lung cancer survive for about 1 year; less than seven percent survive 5 years.

Non-small cell lung cancer is divided into three main subtypes: adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Adenocarcinoma arises from the cells that line the small air sacs (alveoli) located throughout the lungs. Squamous cell carcinoma arises from squamous cells that line the passages leading from the windpipe (trachea) to the lungs (bronchi). Large cell carcinoma arises from epithelial cells that line the lungs. Large cell carcinoma encompasses non-small cell lung cancers that do not appear to be adenocarcinomas or squamous cell carcinomas. The 5-year survival rate for people with non-small cell lung cancer is usually between 11 and 17 percent; it can be lower or higher depending on the subtype and stage of the cancer.

", "ghr_link": "https://ghr.nlm.nih.gov/condition/lung-cancer" }, { "name": "Melanoma", "html_text": "

Melanoma is a type of skin cancer that begins in pigment-producing cells called melanocytes. This cancer typically occurs in areas that are only occasionally sun-exposed; tumors are most commonly found on the back in men and on the legs in women. Melanoma usually occurs on the skin (cutaneous melanoma), but in about 5 percent of cases it develops in melanocytes in other tissues, including the eyes (uveal melanoma) or mucous membranes that line the body's cavities, such as the moist lining of the mouth (mucosal melanoma). Melanoma can develop at any age, but it most frequently occurs in people in their fifties to seventies and is becoming more common in teenagers and young adults.

Melanoma may develop from an existing mole or other normal skin growth that becomes cancerous (malignant); however, many melanomas are new growths. Melanomas often have ragged edges and an irregular shape. They can range from a few millimeters to several centimeters across. They can also be a variety of colors: brown, black, red, pink, blue, or white.

Most melanomas affect only the outermost layer of skin (the epidermis). If a melanoma becomes thicker and involves multiple layers of skin, it can spread to other parts of the body (metastasize).

A large number of moles or other pigmented skin growths on the body, generally more than 25, is associated with an increased risk of developing melanoma. Melanoma is also a common feature of genetic syndromes affecting the skin such as xeroderma pigmentosum. Additionally, individuals who have previously had melanoma are nearly nine times more likely than the general population to develop melanoma again. It is estimated that about 90 percent of individuals with melanoma survive at least 5 years after being diagnosed.

", "ghr_link": "https://ghr.nlm.nih.gov/condition/melanoma" }, { "name": "Multiple Myeloma", "html_text": "

Multiple myeloma is a cancer that develops in the bone marrow, the spongy tissue found in the center of most bones. The bone marrow produces red blood cells, which carry oxygen throughout the body; white blood cells, which form the body's defenses (immune system); and platelets, which are necessary for blood clotting.

Multiple myeloma is characterized by abnormalities in plasma cells, a type of white blood cell. These abnormal cells multiply out of control, increasing from about one percent of cells in the bone marrow to the majority of bone marrow cells. The abnormal cells form tumors within the bone, causing bone pain and an increased risk of fractures. If the tumors interfere with nerves near the bones, numbness or weakness in the arms or legs can occur. Affected individuals may also experience a loss of bone tissue, particularly in the skull, spine, ribs, and pelvis. The deterioration of bone can result in an excess of calcium in the blood (hypercalcemia), which can lead to nausea and loss of appetite, excessive thirst, fatigue, muscle weakness, and confusion.

The abnormal plasma cells in multiple myeloma produce proteins that impair the development of normal blood cells. As a result, affected individuals may have a reduced number of red blood cells (anemia), which can cause fatigue, weakness, and unusually pale skin (pallor); a low number of white blood cells (leukopenia), which can result in a weakened immune system and frequent infections such as pneumonia; and a reduced number of platelets (thrombocytopenia), which can lead to abnormal bleeding and bruising. Kidney problems can also occur in this disorder, caused by hypercalcemia or by toxic proteins produced by the abnormal plasma cells.

People with multiple myeloma typically develop the disorder around age 65. Over time, affected individuals can develop life-threatening complications, but the rate at which this happens varies widely. Some affected individuals are diagnosed incidentally when tests are done for other purposes and do not experience symptoms for years.

", "ghr_link": "https://ghr.nlm.nih.gov/condition/multiple-myeloma" }, { "name": "Noonan Syndrome", "html_text": "

Noonan syndrome is a condition that affects many areas of the body. It is characterized by mildly unusual facial features, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms.

People with Noonan syndrome have distinctive facial features such as a deep groove in the area between the nose and mouth (philtrum), widely spaced eyes that are usually pale blue or blue-green in color, and low-set ears that are rotated backward. Affected individuals may have a high arch in the roof of the mouth (high-arched palate), poor teeth alignment, and a small lower jaw (micrognathia). Many children with Noonan syndrome have a short neck, and both children and adults may have excess neck skin (also called webbing) and a low hairline at the back of the neck.

Between 50 and 70 percent of individuals with Noonan syndrome have short stature. At birth, they are usually a normal length and weight, but growth slows over time. Abnormal levels of growth hormone, a protein that is necessary for the normal growth of the body's bones and tissues, may contribute to the slow growth.

Individuals with Noonan syndrome often have either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum). Some affected people may also have an abnormal side-to-side curvature of the spine (scoliosis).

Most people with Noonan syndrome have some form of critical congenital heart disease. The most common heart defect in these individuals is a narrowing of the valve that controls blood flow from the heart to the lungs (pulmonary valve stenosis). Some have hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle.

A variety of bleeding disorders have been associated with Noonan syndrome. Some affected individuals have excessive bruising, nosebleeds, or prolonged bleeding following injury or surgery. Rarely, women with Noonan syndrome who have a bleeding disorder have excessive bleeding during menstruation (menorrhagia) or childbirth.

Adolescent males with Noonan syndrome typically experience delayed puberty. They go through puberty starting at age 13 or 14 and have a reduced pubertal growth spurt that results in shortened stature. Most males with Noonan syndrome have undescended testes (cryptorchidism), which may contribute to infertility (inability to father a child) later in life. Females with Noonan syndrome can experience delayed puberty but most have normal puberty and fertility.

Noonan syndrome can cause a variety of other signs and symptoms. Most children diagnosed with Noonan syndrome have normal intelligence, but a few have special educational needs, and some have intellectual disability. Some affected individuals have vision or hearing problems. Affected infants may have feeding problems, which typically get better by age 1 or 2 years. Infants with Noonan syndrome may be born with puffy hands and feet caused by a buildup of fluid (lymphedema), which can go away on its own. Older individuals can also develop lymphedema, usually in the ankles and lower legs.

Some people with Noonan syndrome develop cancer, particularly those involving the blood-forming cells (leukemia). It has been estimated that children with Noonan syndrome have an eightfold increased risk of developing leukemia or other cancers over age-matched peers.

Noonan syndrome is one of a group of related conditions, collectively known as RASopathies. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway. In addition to Noonan syndrome, the RASopathies include cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, Legius syndrome, and Noonan syndrome with multiple lentigines.

", "ghr_link": "https://ghr.nlm.nih.gov/condition/noonan-syndrome" }, { "name": "Noonan Syndrome With Multiple Lentigines", "html_text": "

Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome) is a condition that affects many areas of the body. As the condition name suggests, Noonan syndrome with multiple lentigines is very similar to a condition called Noonan syndrome, and it can be difficult to tell the two disorders apart in early childhood. However, the features of these two conditions differ later in life. The characteristic features of Noonan syndrome with multiple lentigines include brown skin spots called lentigines that are similar to freckles, heart defects, widely spaced eyes (ocular hypertelorism), a sunken chest (pectus excavatum) or protruding chest (pectus carinatum), and short stature. These features vary, however, even among affected individuals in the same family. Not all individuals with Noonan syndrome with multiple lentigines have all the characteristic features of this condition.

The lentigines seen in Noonan syndrome with multiple lentigines typically first appear in mid-childhood, mostly on the face, neck, and upper body. Affected individuals may have thousands of small dark brown skin spots by the time they reach puberty. Unlike freckles, the appearance of lentigines has nothing to do with sun exposure. In addition to lentigines, people with this condition may have lighter brown skin spots called café-au-lait spots. Café-au-lait spots tend to develop before the lentigines, appearing within the first year of life in most affected people.

Of the people with Noonan syndrome with multiple lentigines who have heart defects, about 80 percent have hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood. The hypertrophic cardiomyopathy most often affects the lower left chamber of the heart (the left ventricle). Up to 20 percent of people with Noonan syndrome with multiple lentigines who have heart problems have a narrowing of the artery from the heart to the lungs (pulmonary stenosis).

People with Noonan syndrome with multiple lentigines can have a distinctive facial appearance. In addition to ocular hypertelorism, affected individuals may have droopy eyelids (ptosis), thick lips, and low-set ears. Affected individuals also usually have an abnormal appearance of the chest; they either have pectus excavatum or pectus carinatum.

At birth, people with Noonan syndrome with multiple lentigines are typically of normal weight and height, but in some, growth slows over time. This slow growth results in affected individuals being shorter than average, although less than half of people with Noonan syndrome with multiple lentigines have significantly short stature.

Other signs and symptoms of Noonan syndrome with multiple lentigines include hearing loss caused by abnormalities in the inner ear (sensorineural deafness), mild intellectual disability, and extra folds of skin on the back of the neck. Affected males often have genital abnormalities, which can include undescended testes (cryptorchidism) and a urethra that opens on the underside of the penis (hypospadias). These abnormalities may reduce the ability to have biological children (decreased fertility). Females with Noonan syndrome with multiple lentigines may have poorly developed ovaries and delayed puberty.

Noonan syndrome with multiple lentigines is one of a group of related conditions collectively known as RASopathies. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway. In addition to Noonan syndrome with multiple lentigines, the RASopathies include Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, and Legius syndrome.

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test that requires a virtual gene panel for rare disease in the Test Directory." } ], "currentversion": "2.0", "relevant_disorders": [ { "name": "Craniosynostosis syndromes", "id": 18446744073709551615 }, { "name": "Craniosynostosis syndromes phenotypes", "id": 18446744073709551615 }, { "name": "Rare syndromic craniosynostosis or isolated multisuture synostosis", "id": 18446744073709551615 }, { "name": "R100", "id": 18446744073709551615 } ] }, "genelistdescription": "Skeletal disorders, Craniosynostosis syndromes", "levelofconfidence": "3", "penetrance": null, "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted", "modeofpathogenicity": null, "evidences": [ "Expert Review Green", "NHS GMS" ], "phenotypes": [ "cardiofaciocutaneous syndrome type 115150", "Noonan syndrome type 7 613706" ], "pub_med_references": [ 28650561 ] }, { "genecolorreview": "Green", "panelid": "259", "genelistname": "Childhood_solid_tumours_cancer_susceptibility.PanelApp.20191105", "genelistotherdata": { "types": [ { "name": "Cancer Germline 100K", "description": "Cancer Germline 100K" } ], "currentversion": "1.5", "relevant_disorders": [ { "name": "Childhood;Childhood solid tumours pertinent cancer susceptibility", "id": 18446744073709551615 } ] }, "genelistdescription": "Cancer Programme, Pertinent cancer susceptibility gene panel", "levelofconfidence": "3", "penetrance": "Complete", "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown", "modeofpathogenicity": "Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments", "evidences": [ "Expert Review Green", "Expert list" ], "phenotypes": [ "Cardiofaciocutaneous syndrome" ], "pub_med_references": [ 23875798 ] }, { "genecolorreview": "Green", "panelid": "749", "genelistname": "Cardiomyopathies_-_including_childhood_onset.PanelApp.20191105", "genelistotherdata": { "types": [ { "name": "GMS Rare Disease Virtual", "description": "This is a panel for the Genomic Medicine Service for an exome/genome/panel based test that requires a virtual gene panel for rare disease in the Test Directory." }, { "name": "GMS Rare Disease", "description": "This panel type is used for GMS panels that are not virtual (i.e. could be a wet lab test)" } ], "currentversion": "0.13", "relevant_disorders": [ { "name": "Paediatric or syndromic cardiomyopathy", "id": 18446744073709551615 }, { "name": "R135", "id": 18446744073709551615 } ] }, "genelistdescription": null, "levelofconfidence": "3", "penetrance": null, "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted", "modeofpathogenicity": "Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments", "evidences": [ "Expert List", "South West GLH", "London South GLH", "Expert Review Green" ], "phenotypes": [ "Noonan syndrome 7 613706", "Cardio-facio-cutaneous syndrome", "Cardiofaciocutaneous syndrome 115150", "Noonan Syndrome", "syndromic HCM", "Cardiofaciocutaneous Syndrome", "LEOPARD Syndrome", "LEOPARD syndrome 3", "LEOPARD syndrome 3 613707" ], "pub_med_references": [ 19206169, 21396583 ] }, { "genecolorreview": "Amber", "panelid": "245", "genelistname": "Adult_solid_tumours_cancer_susceptibility.PanelApp.20191105", "genelistotherdata": { "types": [ { "name": "Cancer Germline 100K", "description": "Cancer Germline 100K" }, { "name": "GMS Cancer Germline Virtual", "description": "This is a panel used for WGS germline analysis for the GMS." } ], "currentversion": "1.7", "relevant_disorders": [ { "name": "Carcinoma of unknown primary", "id": 18446744073709551615 }, { "name": "Other", "id": 18446744073709551615 }, { "name": "Adult solid tumours pertinent cancer susceptibility", "id": 18446744073709551615 } ] }, "genelistdescription": "Cancer Programme, Pertinent cancer susceptibility gene panel", "levelofconfidence": "2", "penetrance": null, "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown", "modeofpathogenicity": null, "evidences": [ "Expert Review Amber", "NHS GMS" ], "phenotypes": [ "Cardiofaciocutaneous syndrome 115150", "Noonan syndrome 7 613706", "LEOPARD syndrome 3 613707" ], "pub_med_references": [ 23875798 ] } ] }, "transcripts": [ { "name": "NM_004333.6", "strand": "-", "chromo": "chr7", "position": 140430465, "length": 194265, "mrna_length": 6459, "coding_length": 2301, "canonical": true, "cytoband": "7q34", "ensembl_support_level": null }, { "name": "NM_001354609.2", "strand": "-", "chromo": "chr7", "position": 140419137, "length": 205593, "mrna_length": 9687, "coding_length": 2304, "canonical": null, "cytoband": "7q34", "ensembl_support_level": null }, { "name": "NR_148928.2", "strand": "-", "chromo": "chr7", "position": 140430465, "length": 194265, "mrna_length": 7332, "coding_length": null, "canonical": null, "cytoband": "7q34", "ensembl_support_level": null }, { "name": "ENST00000496384.2", "strand": "-", "chromo": "chr7", "position": 140419127, "length": 63831, "mrna_length": 8294, "coding_length": 1125, "canonical": null, "cytoband": "7q34", "ensembl_support_level": "5" }, { "name": "ENST00000288602.6", "strand": "-", "chromo": "chr7", "position": 140434279, "length": 190286, "mrna_length": 2480, "coding_length": 2301, "canonical": true, "cytoband": "7q34", "ensembl_support_level": "1" }, { "name": "ENST00000479537.1", "strand": "-", "chromo": "chr7", "position": 140434321, "length": 19691, "mrna_length": 743, "coding_length": null, "canonical": null, "cytoband": "7q34", "ensembl_support_level": "5" }, { "name": "ENST00000497784.1", "strand": "-", "chromo": "chr7", "position": 140434397, "length": 190062, "mrna_length": 2336, "coding_length": null, "canonical": null, "cytoband": "7q34", "ensembl_support_level": "5" }, { "name": "ENST00000469930.1", "strand": "-", "chromo": "chr7", "position": 140533861, "length": 90649, "mrna_length": 1058, "coding_length": null, "canonical": null, "cytoband": "7q34", "ensembl_support_level": "2" } ], "weill_cornell_medicine_pmkb": { "version": "19_dec_2018", "items": [ { "tier": 2, "definition": [ "BRAF V600D", "BRAF V600E", "BRAF V600K", "BRAF V600R", "BRAF codon(s) 600 any", "BRAF any mutation" ], "interpretations": "B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Mutations of B-RAF have been described in up to 100% of Hairy cell leukemia, 40-70% of Langerhans cell histiocytosis, approximately 50% of Erdheim-Chester disease, approximately 5% of diffuse large B cell lymphoma and plasma cell neoplasms and less than 5% of chronic lymphocytic leukemia. While some reports have found that 10-20% of cases of acute leukemias (ALL or AML) may have BRAF mutations, other reports have described no BRAF in those diseases or in myeloid diseases such as MDS or CML. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain clinical settings. ", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "Acute Myeloid Leukemia", "Atypical Chronic Myeloid Leukemia", "B Lymphoblastic Leukemia/Lymphoma", "Chronic Lymphocytic Leukemia", "Chronic Myeloid Leukemia", "Chronic Myelomonocytic Leukemia", "Chronic Neutrophilic Leukemia", "Diffuse Large B Cell Lymphoma", "Essential Thrombocythemia", "Mast Cell Neoplasm", "MDS with Ring Sideroblasts", "Myelodysplastic Syndrome", "Myeloproliferative Neoplasm", "Polycythemia Vera", "Primary Myelofibrosis", "T Lymphoblastic Leukemia/Lymphoma", "Leukocytosis", "Thrombocytosis", "Monocytosis", "Cytopenia", "Other Acute Leukemia", "Acute Leukemia of Unspecified Cell Type", "Anemia", "Unspecified", "Leukopenia", "Thrombocytopenia", "Eosinophilia", "Myelodysplastic/Myeloproliferative Neoplasm", "Myeloid Neoplasm", "Polycythemia" ], "disease_or_trait": null, "pub_med_references": [ 22230299, 22639828, 23009221, 23088640, 24428489 ], "variants": [ { "type": "variantId", "definition": "BRAF V600D", "gene_id": 2273, "variants": [ "10190071404531350005", "10190071404531350006", "10380071407533350005", "10380071407533350007" ] }, { "type": "variantId", "definition": "BRAF V600E", "gene_id": 2273, "variants": [ "10190071404531360004", "10380071407533360004" ] }, { "type": "variantId", "definition": "BRAF V600K", "gene_id": 2273, "variants": [ "10190071404531360006", "10380071407533360006" ] }, { "type": "variantId", "definition": "BRAF V600R", "gene_id": 2273, "variants": [ "10190071404531360005", "10190071404531360007", "10380071407533360005", "10380071407533360007" ] }, { "type": "codon", "definition": "BRAF codon(s) 600 any", "coding_impact": "any", "gene_id": 2273, "aa_positions": [ 600 ] }, { "type": "any mutation", "gene_id": 2273, "definition": "BRAF any mutation" } ] } ] }, "unil_domino": { "version": "04_sep_2019", "lda_score": 2.2441200000000006, "numberdonor_numbersynonymous": 0.0, "phylop_at_5_prime_utr": 0.20521400000000004, "probability_of_ad": 0.993846, "string_combined_score": 5, "string_experimental_score": 2, "string_text_mining_score": 3, "mrna_half_life": 0 } }