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FBXW7
Variants
VariantGeneTypeCOSMIC IDDNA Change (Coding Nucleotide)Exon
FBXW7 R479QFBXW7missense10
FBXW7 D761NFBXW7missense12
FBXW7 copy number gainFBXW7CNV
FBXW7 copy number lossFBXW7CNV
FBXW7 any mutationFBXW7any
FBXW7 codon(s) 505, 465 missenseFBXW7missense10, 9
FBXW7 R505CFBXW7missense10
FBXW7 R505GFBXW7missense10
FBXW7 R393*FBXW7nonsense8
FBXW7 H500YFBXW7missenseCOSM360091710
FBXW7 R465HFBXW7missense9

Interpretations

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Tier 1
FBXW7
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
B Lymphoblastic Leukemia/Lymphoma
Chronic Lymphocytic Leukemia
Interpretation

FBXW7 is a ubiquitin protein ligase subunit which regulates levels of NOTCH, cyclin E, and other proteins. Loss-of-function mutations of FBXW7 lead to constitutive Notch1 pathway activation via inhibition of ubiquitin-mediated degradation of activated NOTCH1 and MYC. Mutations of FBXW7 include missense and frameshift mutations. FBXW7 have been reported in approximately 4-30% of cases of T-ALL less than 5% of cases of B-ALL, less than 5% of cases of CLL and appear to be very rare/absent in acute myeloid leukemia. According to some, but not all studies, NOTCH1 pathway activation by NOTCH1 mutations or FBXW7 mutations in TALL have been associated with an improved prognosis (in cases without concomitant RAS or PTEN mutations) compared to cases without mutations in NOTCH1 or FBXW7. FBXW7 mutations may occur alone or together with mutations in NOTCH1 (typically those in the heterodimerization domain and more rarely those in the PEST domain of NOTCH1). FBXW7 mutations may result in resistance to gamma secretase inhibitors according to some experimental studies.

Last updated: 2016-06-04 22:13:22 UTC
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Tier 3
FBXW7
Variants
FBXW7 R479Q
FBXW7 D761N
Primary Sites
Breast
Lung
Colon
Stomach
Rectum
Endometrium
Tumor Types
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene that is mutated in several tumors including colorectal, liver, bladders and ovarian cancers. It is also mutated in endometrial and head and neck squamous cancers. Preclinical data suggest that FBXW7 mutations may sensitize cells to mTOR inhibitors.

Last updated: 2016-06-05 02:49:13 UTC
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Tier 3
FBXW7
Variants
FBXW7 R479Q
FBXW7 D761N
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

FBXW7 is a tumor suppressor gene and is responsible for ubiquitination and turnover of several oncoprotiens. Loss-of-function mutations of FBXW7 lead to constitutive NOTCH1 pathway activation via inhibition of ubiquitin-mediated degradation of activated NOTCH1 and MYC. FBXW7 mutations have been reported in ~3-8% of melanomas. Preclinical data suggest that FBXW7 mutations sensitize cells to mTOR inhibitors. However, advanced tumors with somatic FBXW7 mutations and other concurrent molecular alterations might have limited therapeutic response to mTOR inihibitors. Correlation with other clinical and laboratory findings is recommended.

Last updated: 2017-04-10 18:33:50 UTC
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Tier 2
FBXW7
Variants
FBXW7 copy number gain
FBXW7 copy number loss
Primary Sites
Adrenal Gland
Anus
Ampulla (Pancreaticobiliary Duct)
Appendix
Bladder
Blood
Bone
Bone Marrow
Brain
Breast
Spinal Cord
Cervix
Chest Wall
Colon
Endometrium
Esophagus
Eye
Fallopian Tube
Fibroadipose Tissue
Gall Bladder
Kidney
Larynx
Liver
Lung
Lymph Node
Nasal Cavity
Oral Cavity
Ovary
Pancreas
Parathyroid
Penis
Peripheral Nervous System
Peritoneum
Pharynx
Pituitary
Placenta
Pleura
Prostate
Retroperitoneum
Salivary Gland
Seminal Vesicle
Skeletal Muscle
Skin
Small Intestine
Soft Tissue
Spleen
Stomach
Testis
Thymus
Thyroid
Tonsil
Unknown
Ureter
Uterus
Vagina
Rectum
Cartilage
Blood Vessel
Buccal Swab
Heart
Trachea
Salivary Duct
Spermatic Cord
Vulva
Brain, Infratentorial
Brain, Supratentorial
Gastroesophageal Junction
Sellar
Suprasellar
Peritoneal fluid
Pleural Fluid
Tongue
Tumor Types
Acinar Cell Carcinoma
Acinic Cell Carcinoma
Acute Myeloid Leukemia
Adenocarcinoma
Adenoid Cystic Carcinoma
Adenosarcoma
Ameloblastic Tumor
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-Cell Lymphoma
Angiomatoid Fibrous Histiocytoma
Angiomatosis
Angiomyolipoma
Angiosarcoma
Astrocytoma, Anaplastic
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Basal Cell Carcinoma
Burkitt Lymphoma
Carcinoid Tumor
Carcinoma
Carcinosarcoma
Cholangiocarcinoma
Chondrosarcoma
Chordoma
Choriocarcinoma
Chromophobe Renal Cell Carcinoma
Chronic Lymphocytic Leukemia
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Classical Hodgkin Lymphoma
Clear Cell Carcinoma
Clear Cell Renal Cell Carcinoma
Craniopharyngioma
Dermatofibrosarcoma
Desmoplastic Small Round Cell Tumor
Diffuse Large B Cell Lymphoma
Ductal Carcinoma
Ependymoma
Essential Thrombocythemia
Ewing Sarcoma
Fibromatosis
Follicular Carcinoma
Follicular Lymphoma
Gastrointestinal Stromal Tumor
Germ Cell Tumor
Giant Cell Tumor
Glioblastoma
Glomus Tumor
Granular Cell Tumor
Hairy Cell Leukemia
Hemangioendothelioma
Hepatocellular Carcinoma
Histiocytic and Dendritic Cell Neoplasms
Invasive Ductal Carcinoma
Kaposi Sarcoma
Langerhans Cell Histiocytosis
Leiomyoma
Leiomyosarcoma
Lipoma
Liposarcoma
Lobular Carcinoma
Lymphoplasmacytic Lymphoma
Malignant Mullerian Mixed Tumor
Mantle Cell Lymphoma
Marginal Zone B Cell Lymphoma
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Medullary Carcinoma
Medulloblastoma
Melanoma
Meningioma
Merkel Cell Carcinoma
Mesothelioma
Mucinous Adenocarcinoma
Mucinous Tumors of Ovary
Mucoepidermoid Carcinoma
Myelodysplastic Syndrome
Myeloproliferative Neoplasm
Myxofibrosarcoma
Nasopharyngeal Carcinoma
Neuroblastoma
Neuroendocrine Carcinoma
Neuroendocrine Neoplasm
NK Cell Lymphoproliferative Disorder
NLPHL
Non-Small Cell Lung Carcinoma
Oligodendroglioma
Osteosarcoma
Papillary Carcinoma
Papillary Renal Cell Carcinoma
Peripheral T Cell Lymphoma
Pheochromocytoma
Plasma Cell Disorder
Polycythemia Vera
Post-Transplant Lymphoproliferative Disorder
Primary Myelofibrosis
Primitive Neuroectodermal Tumor
Renal Cell Carcinoma
Reninoma
Retinoblastoma
Rhabdomyosarcoma
Sarcoma
Schwannoma
Serous Carcinoma
Sex Cord Stromal Tumor
Small Cell Carcinoma
Solid Pseudopapillary Tumor of Pancreas
Spindle Cell Neoplasm
Squamous Cell Carcinoma
T Cell Lymphoproliferative Disorder
T Lymphoblastic Leukemia/Lymphoma
T-Cell LGL Leukemia
Thymic Carcinoma
Thymoma
Urothelial Carcinoma
Tumors of Peripheral Nerves
Unknown
Wilms Tumor
Ependymoma, Anaplastic
Astrocytoma, Pilocytic
Ganglioglioma
Neuroepithelial Neoplasm, NOS
Pleomorphic Carcinoma
Solitary Fibrous Tumor
Neuroepithelial neoplasm, high grade
Leukocytosis
Thrombocytosis
Monocytosis
Cytopenia
Other Acute Leukemia
Astrocytoma, NOS
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Astrocytoma, Diffusely Infiltrating
Diffuse Midline Glioma
Infiltrating Glioma, NOS
Intraductal Papillary Mucinous Neoplasm (IPMN)
Leukopenia
Lymphadenopathy
Lymphocytosis, Symptomatic
Monoclonal Gammopathy
Mucinous or Serous Cystic Neoplasms of Pancreas
Mycosis Fungoides, Unspecified Site
Oligodendroglioma, Anaplastic
Pleomorphic Xanthoastrocytoma
Rash and Other Nonspecific Skin Eruption
Thrombocytopenia, Unspecified
Eosinophilia
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Polycythemia
Hurthle Cell Carcinoma
High Grade Glioma
Undifferentiated Sarcoma
Glioma
Interpretation

This gene is a known cancer gene.

Last updated: 2018-05-17 15:39:24 UTC
Read More
Tier 2
FBXW7
Variants
FBXW7 any mutation
Primary Sites
Adrenal Gland
Anus
Ampulla (Pancreaticobiliary Duct)
Appendix
Bladder
Blood
Bone
Bone Marrow
Brain
Breast
Spinal Cord
Cervix
Chest Wall
Colon
Endometrium
Esophagus
Eye
Fallopian Tube
Fibroadipose Tissue
Gall Bladder
Kidney
Larynx
Liver
Lung
Lymph Node
Nasal Cavity
Oral Cavity
Ovary
Pancreas
Parathyroid
Penis
Peripheral Nervous System
Peritoneum
Pharynx
Pituitary
Placenta
Pleura
Prostate
Retroperitoneum
Salivary Gland
Seminal Vesicle
Skeletal Muscle
Skin
Small Intestine
Soft Tissue
Spleen
Stomach
Testis
Thymus
Thyroid
Tonsil
Unknown
Ureter
Uterus
Vagina
Rectum
Cartilage
Blood Vessel
Buccal Swab
Heart
Trachea
Salivary Duct
Spermatic Cord
Vulva
Brain, Infratentorial
Brain, Supratentorial
Gastroesophageal Junction
Sellar
Suprasellar
Peritoneal fluid
Pleural Fluid
Tongue
Tumor Types
Acinar Cell Carcinoma
Acinic Cell Carcinoma
Acute Myeloid Leukemia
Adenocarcinoma
Adenoid Cystic Carcinoma
Adenosarcoma
Ameloblastic Tumor
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-Cell Lymphoma
Angiomatoid Fibrous Histiocytoma
Angiomatosis
Angiomyolipoma
Angiosarcoma
Astrocytoma, Anaplastic
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Basal Cell Carcinoma
Burkitt Lymphoma
Carcinoid Tumor
Carcinoma
Carcinosarcoma
Cholangiocarcinoma
Chondrosarcoma
Chordoma
Choriocarcinoma
Chromophobe Renal Cell Carcinoma
Chronic Lymphocytic Leukemia
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Classical Hodgkin Lymphoma
Clear Cell Carcinoma
Clear Cell Renal Cell Carcinoma
Craniopharyngioma
Dermatofibrosarcoma
Desmoplastic Small Round Cell Tumor
Diffuse Large B Cell Lymphoma
Ductal Carcinoma
Ependymoma
Essential Thrombocythemia
Ewing Sarcoma
Fibromatosis
Follicular Carcinoma
Follicular Lymphoma
Gastrointestinal Stromal Tumor
Germ Cell Tumor
Giant Cell Tumor
Glioblastoma
Glomus Tumor
Granular Cell Tumor
Hairy Cell Leukemia
Hemangioendothelioma
Hepatocellular Carcinoma
Histiocytic and Dendritic Cell Neoplasms
Invasive Ductal Carcinoma
Kaposi Sarcoma
Langerhans Cell Histiocytosis
Leiomyoma
Leiomyosarcoma
Lipoma
Liposarcoma
Lobular Carcinoma
Lymphoplasmacytic Lymphoma
Malignant Mullerian Mixed Tumor
Mantle Cell Lymphoma
Marginal Zone B Cell Lymphoma
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Medullary Carcinoma
Medulloblastoma
Melanoma
Meningioma
Merkel Cell Carcinoma
Mesothelioma
Mucinous Adenocarcinoma
Mucinous Tumors of Ovary
Mucoepidermoid Carcinoma
Myelodysplastic Syndrome
Myeloproliferative Neoplasm
Myxofibrosarcoma
Nasopharyngeal Carcinoma
Neuroblastoma
Neuroendocrine Carcinoma
Neuroendocrine Neoplasm
NK Cell Lymphoproliferative Disorder
NLPHL
Non-Small Cell Lung Carcinoma
Oligodendroglioma
Osteosarcoma
Papillary Carcinoma
Papillary Renal Cell Carcinoma
Peripheral T Cell Lymphoma
Pheochromocytoma
Plasma Cell Disorder
Polycythemia Vera
Post-Transplant Lymphoproliferative Disorder
Primary Myelofibrosis
Primitive Neuroectodermal Tumor
Renal Cell Carcinoma
Reninoma
Retinoblastoma
Rhabdomyosarcoma
Sarcoma
Schwannoma
Serous Carcinoma
Sex Cord Stromal Tumor
Small Cell Carcinoma
Solid Pseudopapillary Tumor of Pancreas
Spindle Cell Neoplasm
Squamous Cell Carcinoma
T Cell Lymphoproliferative Disorder
T Lymphoblastic Leukemia/Lymphoma
T-Cell LGL Leukemia
Thymic Carcinoma
Thymoma
Urothelial Carcinoma
Tumors of Peripheral Nerves
Unknown
Wilms Tumor
Ependymoma, Anaplastic
Astrocytoma, Pilocytic
Ganglioglioma
Neuroepithelial Neoplasm, NOS
Pleomorphic Carcinoma
Solitary Fibrous Tumor
Neuroepithelial neoplasm, high grade
Leukocytosis
Thrombocytosis
Monocytosis
Cytopenia
Other Acute Leukemia
Astrocytoma, NOS
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Astrocytoma, Diffusely Infiltrating
Diffuse Midline Glioma
Infiltrating Glioma, NOS
Intraductal Papillary Mucinous Neoplasm (IPMN)
Leukopenia
Lymphadenopathy
Lymphocytosis, Symptomatic
Monoclonal Gammopathy
Mucinous or Serous Cystic Neoplasms of Pancreas
Mycosis Fungoides, Unspecified Site
Oligodendroglioma, Anaplastic
Pleomorphic Xanthoastrocytoma
Rash and Other Nonspecific Skin Eruption
Thrombocytopenia, Unspecified
Eosinophilia
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Polycythemia
Hurthle Cell Carcinoma
High Grade Glioma
Undifferentiated Sarcoma
Glioma
Interpretation

This gene is a known cancer gene.

Last updated: 2018-05-17 15:40:17 UTC
Read More
Tier 2
FBXW7
Variants
FBXW7 codon(s) 505, 465 missense
Primary Sites
Small Intestine
Tumor Types
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. Codons 465 and 505 are some of the most frequently mutated sites in the FBXW7 gene. FBXW7 is mutated in approximately 15% of small bowel cancers. Preclinical data have suggested that inactivating mutations of FBXW7 could predict sensitivity to the mTOR inhibitor rapamycin; however, the clinical utility remains unknown.

Last updated: 2018-03-06 17:58:08 UTC
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Tier 2
FBXW7
Variants
FBXW7 R479Q
FBXW7 codon(s) 505, 465 missense
Primary Sites
Pancreas
Tumor Types
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene that is mutated in several tumors including colorectal, liver, bladders and ovarian cancers. It is also mutated in endometrial and head and neck squamous cancers. FBXW7 mutations are rare in pancreatic adenocarcinoma and are present in less than 1% of tumors. Preclinical data suggest that FBXW7 mutations may sensitize cells to mTOR inhibitors. The full pathologic significance of FBXW7 mutations in pancreatic adenocarcinoma remains to be more fully elucidated.

Last updated: 2018-03-12 15:41:42 UTC
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Tier 2
FBXW7
Variants
FBXW7 R505C
Primary Sites
Colon
Tumor Types
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. FBXW7 R505C lies within the WD4 repeat region and confers a loss of FBXW7-substrate interaction and impairs substrate degradation by FBXW7, resulting in sustained NICD and MYC expression. Preclinical data have suggested that inactivating mutations of FBXW7 could predict sensitivity to the mTOR inhibitor rapamycin; A single study has reported only limited activity in phase I trials using mTOR inhibitors in patients with advanced cancers including colorectal cancer. The clinical utility remains unknown.

Last updated: 2018-03-21 18:16:22 UTC
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Tier 3
FBXW7
Variants
FBXW7 R505G
Primary Sites
Esophagus
Tumor Types
Squamous Cell Carcinoma
Carcinoma
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene that is mutated in several tumors including colorectal, liver, bladder and ovarian cancers. It is also mutated in endometrial, esophageal, and head and neck squamous cancers. FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. FBXW7 R505G lies within the WD repeat 4 of the FBXW7 protein. R505G has been identified in the scientific literature, but has not been biochemically characterized and therefore, its effect on FBXW7 protein function is unknown. Preclinical data suggest that FBXW7 mutations may sensitize cells to mTOR inhibitors, however, the response to mTOR inhibitors and the clinicopathologic effects of FBXW7 R505G remains to be further elucidated.

Last updated: 2018-04-02 16:07:40 UTC
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Tier 2
FBXW7
Variants
FBXW7 R393*
Primary Sites
Colon
Tumor Types
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. Due to the disruption of the WD repeat domain, the FBXW7 R393* truncating mutation is predicted to lead to a loss of FBXW7 protein function. Preclinical data have suggested that inactivating mutations of FBXW7 could predict sensitivity to the mTOR inhibitor rapamycin; however, the clinical utility remains unknown. A single study has reported only limited activity in phase I trials using mTOR inhibitors in patient with advanced cancers including colorectal cancer.

Last updated: 2018-04-18 14:41:45 UTC
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Tier 3
FBXW7
Variants
FBXW7 H500Y
Primary Sites
Bladder
Tumor Types
Urothelial Carcinoma
Interpretation

FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes, and is mutated in several tumors including colorectal, liver, bladders and ovarian cancers. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. FBXW7 loss of function mutations have been described in many types of adenocarcinoma including colon, bladder and lung. FBXW7 mutations are present in approximately 7% of urothelial carcinomas. Preclinical data have suggested that inactivating mutations of FBXW7 could predict sensitivity to the mTOR inhibitor rapamycin. However, this particular variant (H500Y) has not been characterized in the scientific literature. Therefore, the effect on protein function is unknown. Clinical correlation is recommended.

Last updated: 2018-10-11 19:01:24 UTC
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Tier 2
FBXW7
Variants
FBXW7 R505C
Primary Sites
Rectum
Tumor Types
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. FBXW7 R505C lies within the WD4 repeat region and confers a loss of FBXW7-substrate interaction and impairs substrate degradation by FBXW7, resulting in sustained NICD and MYC expression. Preclinical data have suggested that inactivating mutations of FBXW7 could predict sensitivity to the mTOR inhibitor rapamycin. A single study has reported only limited activity in phase I trials using mTOR inhibitors in patients with advanced cancers including colorectal cancer. The clinical utility remains unknown.

Last updated: 2019-01-22 18:35:33 UTC
Read More
Tier 2
FBXW7
Variants
FBXW7 R465H
Primary Sites
Colon
Tumor Types
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes and is inactivated by mutation in various cancers, most frequently in endometrial and colorectal cancers. Substrates of FBXW7 include the proteins c-MYC, mTOR, NOTCH1, cyclin-E, and JUN, which are instrumental in the regulation of cell division, differentiation and growth, and which are often inappropriately activated in cancer. Inactivation of FBXW7 by mutation or copy number loss results in aberrant accumulation of the above oncoproteins, which subsequently contributes to malignant transformation. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. Most mutations in FBXW7 are point mutations that disrupt substrate binding, while <10% are small deletions or insertions. FBXW7 is altered in 17% of colorectal adenocarcinomas. The FBXW7 R465H variant is considered to be likely oncogenic. Preclinical data have suggested that inactivating mutations of FBXW7 could predict sensitivity to the mTOR inhibitor rapamycin. A single study has reported only limited activity in phase I trials using mTOR inhibitors in patients with advanced cancers including colorectal cancer. The clinical utility remains unknown.

Last updated: 2019-01-22 18:39:36 UTC
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Disclaimer: You assume full responsibility for all risks associated with using this PMKB website. The Englander Institute for Precision Medicine at Weill Cornell Medicine makes no guarantee of the comprehensiveness, reliability or accuracy of the information on this website and assumes no responsibility for errors in the information associated with this web site. Healthcare providers and patients must integrate all clinical and laboratory findings as well as information from a variety of sources before deciding on appropriate clinical care options.


When using PMKB, please cite: Huang et al., JAMIA 2017


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