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Genomic Tests and Family History by Levels of Evidence


The CDC Office of Public Health Genomics ranks the following list for levels of evidence of genomic tests and family health history in practice . This approach was based on a paper by Khoury and updated in accordance with criteria presented by a 2014 paper in Clinical Pharmacology and Therapeutics. The criteria are  shown in the following figure to provide additional information to our readers. This list is updated on an ongoing basis andprovided only for informational purposes to researchers, healthcare providers, public health programs and others.

Green
  • FDA label requires use of test to inform choice or dose of a drug
  • CMS covers testing
  • Clinical practice guidelines based on systematic review supports testing

Yellow
  • FDA label mentions biomarkers*
  • CMS coverage with evidence development
  • Clinical practice guideline, not based on systematic review, supports use of test
  • Clinical practice guideline finds insufficient evidence but does not discourage use of test
  • Systematic review, without clinical practice guideline, supports use of test
  • Systematic review finds insufficient evidence but does not discourage use of test
  • Clinical practice guideline recommends dosage adjustment, but does not address testing

Red
  • FDA label cautions against use
  • CMS decision against coverage
  • Clinical practice guideline recommends against use of test
  • Clinical practice guideline finds insufficient evidence and discourages use of test
  • Systematic review recommends against use
  • Systematic review finds insufficient evidence and discourages use
  • Evidence available only from published studies without systematic reviews, clinical practice guidelines, FDA label or CMS labels coverage decision
*Can be reassigned to Green of Red of one or more conditions in these categories apply
Tier 2/Yellow category: represents genomic and family health history applications have synthesized evidence that is insufficient to support routine implementation in practice; however, existing evidence may provide information for informed decision making by providers and patients.

Gene, Gene/Drug, Test, or Family History Disorder/Indication Use* Synthesized Evidence Sources
Cancer—Breast
gene expression profiles breast cancer Recurrence:  risk prediction; prognostic EGAPP (2009)
ER-alpha and PgR status/ER-alpha (ESR1)-modulating agents invasive breast cancer and breast cancer PGx - recurrence risk prediction; prognostic

NCCN Task Force (2011)

NCCN Task Force (2009)

ASCO/CAP (2010)

CYP2D6/tamoxifen risk for primary breast cancer or breast cancer recurrence PGx – informing therapeutic choice BCBSA TEC (2014)
Cancer—Colorectal
first-degree family history of colorectal cancer at a younger age or multiple affected first-degree relatives colorectal cancer screening risk prediction USPSTF (2008)
BRAF c.1799T>A (p.V600E) colon cancer prognostic

NCCN Task Force (2011)

NCCN Guideline [PDF 1.30 MB] (2013)

BRAF V600E/cetuximab, panitumumab metastatic colorectal cancer PGx

EGAPP [PDF 456.16 KB] (2013)

NCCN Task Force (2011)

UGT1A1/irinotecan Metastatic carcinoma of the colon or rectum PGx

FDA-PGx Drug Information (2012)

EGAPP (2009)

testing for Lynch syndrome patients meeting revised Bethesda guidelines or Amsterdam criteria diagnostic, screening

NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)

testing for Lynch syndrome endometrial cancer in women under 50 years of age diagnostic, screening

NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)

consideration of testing for Lynch syndrome people with 5% or higher risk of Lynch syndrome based on any prediction model diagnostic, screening

NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)

testing for Lynch syndrome colorectal cancer diagnosed under 70 years of age, and those 70 and older who meet Bethesda guidelines diagnostic, screening

NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)

testing for Lynch syndrome colorectal cancer in patients younger than 50 years diagnostic, screening

NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)

testing for Lynch syndrome synchronous or metachronous colorectal or other Lynch syndrome-related tumors, at any age diagnostic, screening

NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)

testing for Lynch syndrome MSI-H histology in colorectal cancer patients younger than 60 years diagnostic, screening

NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)

testing for Lynch syndrome colorectal cancer in patient with relative (one or more first-degree) with Lynch syndrome related cancer that was diagnosed under age 50 years diagnostic, screening

NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)

testing for Lynch syndrome colorectal cancer in patient with relatives (two or more first- or second-degree) with Lynch syndrome related cancer at any age diagnostic, screening

NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)

Cancer—Leukemia
FLT3-ITD acute myeloid leukemia predictive; prognostic

NCCN Task Force (2011)

NCCN Guideline [PDF 852.75 KB] (2013)

CEBPA mutation acute myeloid leukemia predictive; prognostic

NCCN Task Force (2011)

NCCN Guideline [PDF 852.78 KB] (2013)

NPM1 mutation acute myeloid leukemia predictive; prognostic

NCCN Task Force (2011)

NCCN Guideline [PDF 852.80 KB] (2013)

KIT mutation acute myeloid leukemia predictive; prognostic

NCCN Task Force (2011)

NCCN Guideline [PDF 852.70 KB] (2013)

Philadelphia chromosome/busulfan chronic myelogenous leukemia PGx FDA-PGx Drug Information (2003)
UGT1A1*28 homozygotes/nilotinib Philadelphia chromosome positive chronic myeloid leukemia PGx FDA-PGx Drug Information (2013)
FIP1L1-PDGFRα kinase/imatinib hypereosinophilic syndrome and/or chronic eosinophilic leukemia PGx-dose FDA-PGx Drug Information (2013)
TPMT/thiopurines (mercaptopurine) acute lymphatic leukemia PGx-dose

CPIC (2011)

FDA-PGx Drug Information (2011)

TPMT/thiopurines (thioguanine) acute, non-lymphocytic leukemias PGx-dose

CPIC (2011)

FDA-PGx Drug Information (2004)

Cancer—Lung
KRAS mutations [except c38G>A]/anti-EGFR therapy non–small cell lung cancer predictive; prognostic NCCN Task Force (2011)
Cancer—Melanoma
G6PD/dabrafenib unresectable or metastatic melanoma PGx FDA-PGx Drug Information (2014)
family history of skin cancer skin cancer screening in adults risk prediction USPSTF (2009)
Cancer—Other
DPD testing/5-FU (capecitabine) Dukes’ C colon cancer, metastatic colorectal cancer, metastatic breast cancer PGx FDA-PGx Drug Information (2013)
family history of bladder cancer bladder cancer screening risk prediction USPSTF (2011)
c-Kit D816V/imatinib aggressive systemic mastocytosis PGx FDA-PGx Drug Information (2013)
TPMT/cisplatin metastatic testicular tumors, metastatic ovarian tumors, advanced bladder cancer PGx FDA-PGx Drug Information (2011)
Cardiovascular
family history relevant to dyslipidemia (otherwise undefined) lipid screening in  infants, children, adolescents, or young adults (up to age 20) risk prediction USPSTF (2007)
first-degree family history of abdominal aortic aneurysm requiring surgical repair abdominal aortic aneurysm screening risk prediction USPSTF (2005)
SLCO1B1/simvastatin dyslipidemia PGx-dose CPIC (2012)
CYP2C9, VKORC1/warfarin venous thrombosis, pulmonary embolism, thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement, myocardial infarction PGx-dose

CMS CED (2009)

ACMG (2008)

FDA-PGx Drug Information

CPIC (2011)

CYP2D6/metoprolol hypertension, angina pectoris, heart failure PGx FDA-PGx Drug Information (2012)
CYP2D6/carvedilol chronic heart failure, left ventricular dysfunction following myocardial infarction, hypertension PGx FDA-PGx Drug Information (2012)
CYP2D6/carvedilol chronic heart failure, left ventricular dysfunction following myocardial infarction, hypertension PGx FDA-PGx Drug Information (2011)
CYP2D6/propafenone atrial fibrillation PGx FDA-PGx Drug Information (2011)
CYP2C19/clopidogrel non-ST-segment elevation acute coronary syndrome, ST-elevation myocardial infarction, myocardial
infarction, stroke, peripheral arterial disease
PGx

FDA-PGx Drug Information (2013)

CPIC (2013)

AHRQ (2013)

CYP2C19/prasugrel acute coronary syndrome managed with percutaneous coronary intervention PGx FDA-PGx Drug Information (2013)
CYP2C19/tricagrelor acute coronary syndrome PGx FDA-PGx Drug Information (2013)
LDLR/pravastatin hypercholesterolemia PGx FDA-PGx Drug Information (2012)
F5, SERPINC1/eltrombopag thrombocytopenia PGx FDA-PGx Drug Information (2012)
Endocrine disorders
G6PD/chlorpropamide glycemic control, type 2 diabetes in adults PGx FDA-PGx Drug Information (2011)
G6PD/glimepiride glycemic control, type 2 diabetes in adults PGx FDA-PGx Drug Information (2013)
G6PD/glipizide glycemic control, type 2 diabetes in adults PGx FDA-PGx Drug Information (2013)
G6PD/glyburide glycemic control, type 2 diabetes in adults PGx FDA-PGx Drug Information (2013)
Gastroenterology
CYP2C19/pantoprazole gastroesophageal reflux disease, pathological hypersecretory conditions PGx-dose FDA-PGx Drug Information (2013)
CYP2C19/omeprazole duodenal ulcer, gastric ulcer, gastroesophageal reflux disease PGx FDA-PGx Drug Information (2013)
CYP2C19/esomeprazole gastroesophageal reflux disease, NSAID-associated gastric ulcer, duodenal ulcer recurrence, pathological hypersecretory
conditions
PGx FDA-PGx Drug Information (2012)
CYP2C19/rabeprazole gastroesophageal reflux disease, duodenal ulcers, pathological hypersecretory conditions PGx FDA-PGx Drug Information (2013)
CYP2C19, CYP1A2/dexlansoprazole erosive esophagitis, heartburn PGx FDA-PGx Drug Information (2013)
Infectious Disease
G6PD/chloroquine phosphate malaria, extraintestinal amebiasis PGx FDA-PGx Drug Information (2013)
G6PD/dapsone (tablet) leprosy PGx

FDA-PGx Drug Information

DailyMed (2011)
G6PD/mafenide acetate (for 5% topical solution) bacterial infections PGx FDA-PGx Drug Information (1998)
G6PD/nitrofurantoin antibacterial, specific urinary tract infections PGx FDA-PGx Drug Information (2013)
G6PD/primaquine vivax malaria, radical cure (prevention of relapse) PGx FDA-PGx Drug Information (2008)
G6PD/quinine sulfate uncomplicated Plasmodium falciparum malaria PGx FDA-PGx Drug Information (2013)
G6PD/sulfamethoxazole & trimethoprim bacterial infections PGx FDA-PGx Drug Information (2013)
IL28B/boceprevir chronic hepatitis C genotype 1 PGx FDA-PGx Drug Information (2013)
IL28B/telaprevir chronic hepatitis C genotype 1 PGx FDA-PGx Drug Information (2013)
IL28B/peginterferon alfa-2b chronic hepatitis C PGx FDA-PGx Drug Information (2013)
CYP2C19/voriconazole  invasive aspergillosis, candidemia and disseminated candidiasis, esophageal candidiasis, Scedosporium apiospermum and Fusarium spp. infection PGx-dose FDA-PGx Drug Information (2011)
Neurology
CYP2C19/clobazam seizures associated with Lennox-Gastaut syndrome PGx-dose FDA-PGx Drug Information (2013)
HLA-B*1502/phenytoin generalized tonic-clonic status epilepticus and for seizures that occur during neurosurgery; testing pertains to risk for certain serious dermatologic reactions, which may be higher in patients of Chinese or Asian ancestry PGx FDA-PGx Drug Information (2013)
HLAB*1502/ carbamazepine epilepsy, other seizure disorders, trigeminal neuralgia, bipolar disorder PGx-dose CPIC (2013)
CYP2D6, CYP2C19/diazepam epilepsy PGx FDA-PGx Drug Information (2005)
CYP2D6/dextromethorphan and quinidine pseudobulbar affect PGx, PGx-dose FDA-PGx Drug Information (2010)
Psychiatry
parental history of depression major depressive disorder screening in adolescents risk prediction USPSTF (2009)
family history of depression depression screening in adults risk prediction USPSTF (2009)
CYP2D6/amitriptyline depression PGx-dose

CPIC (2013)

FDA-PGx Drug Information

CYP2D6/desipramine depression PGx-dose

CPIC (2013)

FDA-PGx Drug Information (2012)

CYP2D6/fluoxetine major depressive disorder, obsessive compulsive disorder, bulimia nervosa, panic disorder PGx FDA-PGx Drug Information (2009)
CYP2D6/imipramine depression PGx-dose

CPIC (2013)

FDA-PGx Drug Information (2012)

CYP2D6/nortriptyline depression PGx-dose

CPIC (2013)

FDA-PGx Drug Information (2012)

CYP2D6/trimipramine depression PGx-dose

CPIC (2013)

FDA-PGx Drug Information (2012)

CYP2D6/venlafaxine major depressive disorder, social anxiety disorder PGx, PGx-dose FDA-PGx Drug Information (2012)
CYP2C19, CYP2D6/citalopram depression PGx-dose FDA-PGx Drug Information (2012)
CYP2D6/aripiprazole schizophrenia, bipolar I disorder, major depressive disorder, autistic disorder PGx-dose FDA-PGx Drug Information (2013)
CYP2D6/clozapine schizophrenia, schizoaffective disorder PGx-dose FDA-PGx Drug Information (2013)
CYP2D6/iloperidone schizophrenia PGx-dose FDA-PGx Drug Information (2013)
CYP2D6/risperidone schizophrenia, bipolar I disorder, autistic disorder PGx-dose FDA-PGx Drug Information (2012)
CYP2D6/atomoxetine attention-deficit/hyperactivity disorder PGx-dose FDA-PGx Drug Information (2013)
CYP2D6/clomipramine obsessive-compulsive disorder PGx-dose

CPIC (2013)

FDA-PGx Drug Information (2012)

CYP2D6, CYP2C19/fluvoxamine obsessive compulsive disorder PGx FDA-PGx Drug Information (2012)
CYP2D6, CYP2C19/doxepin insomnia PGx-dose

CPIC (2013)

FDA-PGx Drug Information (2010)

CYP2D6/modafinil narcolepsy, obstructive sleep apnea, and shift work disorder PGx-dose FDA-PGx Drug Information (2010)
Rheumatology
CYP2C19/carisoprodol musculoskeletal conditions PGx FDA-PGx Drug Information (2013)
CYP2C9/celecoxib osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain, primary dysmenorrhea PGx-dose FDA-PGx Drug Information (2011)
CYP2C9/flurbiprofen rheumatoid arthritis, osteoarthritis PGx FDA-PGx Drug Information (2010)
TPMT/thiopurines (azathioprine) renal homotransplantation, rheumatoid arthritis PGx-dose

CPIC (2011)

FDA-PGx Drug Information (2011)

Other
family history of developmental dysplasia of the hip developmental dysplasia of the hip screening in infants risk prediction USPSTF (2006)
family history of diabetes gestational diabetes screening risk prediction USPSTF (2008)
family history of neonatal jaundice Hyberbilirubinemia screening in infants; prevention of chronic bilirubin encephalopathy risk prediction USPSTF (2009)
family history of age-related macular degeneration visual acuity screening in older adults risk prediction USPSTF (2009)
family history of chronic kidney disease chronic kidney disease screening risk prediction USPSTF (2012)
family history for common diseases common diseases risk prediction NIH State of the Science (2009)
CYP2D6/tolterodine overactive bladder PGx FDA-PGx Drug Information (2012)
HPRT1/mycophenolic acid organ rejection PGx FDA-PGx Drug Information (2013)
CYP2C19/drospirenone and ethinyl estradiol pregnancy prevention, premenstrual dysphoric disorder, moderate acne PGx FDA-PGx Drug Information (2012)
UGT1A1/indacaterol chronic obstructive pulmonary disease, including chronic bronchitis and/or emphysema PGx FDA-PGx Drug Information (2012)
CYP2D6/codeine pain PGx-dose

CPIC (2012)

FDA-PGx Drug Information (2013)

CYP2D6/tramadol and acetaminophen acute pain PGx

FDA-PGx Drug Information (2013)

CYP2D6/cevimeline dry mouth in patients with Sjögren’s Syndrome PGx FDA-PGx Drug Information (2013)
DPD/fluorouracil cream multiple
actinic or solar keratoses
PGx FDA-PGx Drug Information (2003)
G6PD/dapsone (gel) acne vulgaris PGx FDA-PGx Drug Information (2009)
G6PD/dapsone (tablet) dermatitis herpetiformis PGx

FDA-PGx Drug Information

DailyMed (2011)
G6PD/(polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, & ascorbice acid for oral solution) laxative, preparation for colonoscopy in adults PGx FDA-PGx Drug Information (2013)
G6PD/sodium nitrite life-threatening, acute cyanide poisoning PGx FDA-PGx Drug Information (2012)
G6PD/succimer lead poisoning, pediatric PGx FDA-PGx Drug Information (2007)
next generation sequencing/whole genome sequence various rare familial diseases diagnostic BCBS TEC [PDF 210.52 KB] (2013)
various molecular, cytogenetic biochemical and other tests** single gene disorders and chromosomal abnormalities where diagnosis and management may require use of genetic tests even without formal evidence synthesis and reviews by evidence panels diagnosis, management, carrier testing NIH GTR (2013)

*Pharmacogenomic applications have been classified in the Use column as either PGx (which may relate to drug choice, prevention of adverse events, or other uses of the information gained through testing), or PGx-dose (when specific dosing-related guidance is provided, or mention of a potential effect on dose is noted in the evidence sources cited). Additional Use categories include: screening, cascade testing, risk prediction, diagnostic, and prognostic.

**This entry includes many genetic disorders for which there are no evidence-based recommendations, clinical guidelines or systematic reviews. However, a systematic search for evidence-based recommendations and reviews has not been conducted to date by our office. We expect further refinements in this classification in the near future.

Source Abbreviations: Agency for Healthcare Research and Quality (AHRQ), American College of Medical Genetics and Genomics (ACMG), American Society of Clinical Oncology (ASCO), Centers for Medicare and Medicaid Services (CMS), Clinical Pharmacogenetics Implementation Consortium (CPIC), Evaluation of Genomic Applications in Practice and Prevention (EGAPP), National Comprehensive Cancer Network (NCCN), National Institute for Health and Care Excellence (NICE), National Institutes of Health (NIH), Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC), US Department of Health and Human Services (DHHS), US Food and Drug Administration (FDA), United States Preventive Services Task Force (USPSTF)

Other Abbreviations: estrogen receptor (ER), progesterone receptor (PgR), pharmacogenomics (PGx), single-nucleotide polymorphism (SNP)

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