Are procedures that include surgical manipulation of the maxilla and /or the mandible to restore the correct anatomical and functional relationship in those patients that present skeletal-dental facial anomalies. These anomalies may be present at birth, as the individual grows and develops or may be the result of traumatic injuries. <a id="

The oral splints are molds manufactured by the Oral and Maxillofacial Surgeon prior to surgery. These molds are used as a guide for the replacement of the mandibular and maxillary segments (after these have been segmented). The splint can also be used to stabilize the segments after surgery. <a id="

The thiopurine class of drugs, which include azathioprine (a pro-drug for mercaptopurine), mercaptopurine, and thioguanine, are used to treat a variety of diseases; however, it is recommended the use of thiopurines be limited due to a high rate of drug toxicity. The TPMT and NUDT15 genes encode for the enzymes thiopurine S-methyltransferase (TPMT) and Nudix Hydrolase (NUDT15), respectively. These enzymes are involved in the metabolism of thiopurines. Genetic variants in TPMT and NUDT15 genes affect drug hydrolysis and hence, increase susceptibility to drug-induced toxicity. Mercaptopurine and thioguanine are directly metabolized by the TPMT enzyme. Susceptibility to drug toxicity is linked to the level of TPMT activity. The variation in TPMT activity has been related to 3 distinct TPMT variants. TPMT can be assessed through genetic analysis for polymorphisms in leukocyte DNA (genotype) or by measurement of the enzyme activity in circulating red blood cells (RBCs; phenotype). NUDT15 is measured by genetic analysis only (genotype). Pharmacogenomic analysis of TPMT/NUDT15 status is proposed to identify individuals at risk of thiopurine drug toxicity and adjustment of medication doses accordingly. Measurement of metabolite markers has also been proposed.

As highlighted in a 2008 editorial, the ongoing difficulties with using molecular techniques to detect metastases in sentinel lymph nodes include 1) the uncertainty of the clinical significance of RT-PCRpositive but histologically and immunohistochemically negative sentinel lymph nodes; 2) the issue of possible false positives with a test as sensitive as RT-PCR; 3) the exact size of the metastasis cannot be determined because the tissue is digested in preparation for RT-PCR; and 4) the possibility that the assay is detecting small amounts of benign epithelial cells in the lymph node instead of metastatic carcinoma. (22) What is still not clear is the clinical utility of using molecular methods to detect sentinel lymph node metastases in making patient management decisions. <a id="

Maxillary obturators are considered a maxillofacial prosthesis. Maxillary prosthetic devices are generally removable and are used to correct palatal or nasopharyngeal defects. These defects may be congenital, pathological or may be the result of trauma or surgery. The treatment goal is to restore function (chew, swallow, speech) and a normal appearance of the face. This is achieved by artificially closing the defect using a prosthetic obturator or through surgical reconstruction of the defect. <a id="

It is the surgical procedure of the extirpation, dissection or muscular liberation of the frenulum that causes ankyloglosia, diastema, problems in; speech phonetics, lactation, poor retention of prostheses and periodontal such as, loss of adherent gingiva. We have upper lip frenulum, lower lip frenulum, lingual frenulum and lateral maxillary and mandibular frenulum. <a id="

These are specialized and extensive prosthesis services to replace the loss of a great part of the facial and oral tissue caused by, disease, trauma, surgery, radiation and birth defects. <a id="

When a participating dentist leaves his office to perform dental services in an Ambulatory Surgical Center or Hospital. <a id="

The crown on implants is a fixed prosthesis that is placed on an osseointegrated implant. Retainers of bridges / pontics on implants are a series of crowns which replaces one or more edentulous spaces resting on osseointegrated implants. Retainers hold the bridge on top of implants and the pontics are placed in the edentulous spaces. The prosthesis supported by implant may be complete or partial and they rest on a series of implants returning the functionality of the mouth, restoring mastication and phonetics. <a id="

Dental implants are attachments that replace the root function of a tooth that are placed in the edentulous spaces to replace missing teeth. They are made of materials (titanium) capable of osseointegration in order to coexist in a healthy and natural way with the rest of the tissues of the mouth. After the bone integration of the implant occurs, a crown or prosthesis will be constructed on top of them. <a id="

Periodontal non- surgical services include all post-operative care. They are a range of therapeutic procedures to solve problems of gums and splinting of teeth. <a id="

The main objective of the periodontal surgical procedures is to be able to preserve the periodontal tissues for a long term. With scaling and root planning in conjunction with periodontal surgeries. <a id="

It is remaking of a contaminated endodontic, in a tooth with a previously root canal treatment. <a id="

They are components that help with the construction of fixed partial dentures when the condition or position of the teeth does not help to perform it the conventional way. These techniques help when: Stress breaker are used as an integral part of a partial denture that will enable the operator to limit the movements between the clasps on the abutment teeth and the free end saddle to such a degree that the movement will be within the physiologic tolerance of the underlying tissues and equalize the stress between the abutment teeth and edentulous area Precision Attachment is use when the abutment is at an angle out of the parallelism of the passage of insertion. <a id="

Fixed partial denture is a series of crowns that replace one or more of the edentulous spaces. Retainers or abutments are crowns that hold the bridge on the extremes over the teeth. The pontic is the crown that replaces the edentulous space. <a id="

It is an artificial removable device designed to restore the anatomy of one, several or all the teeth, restoring the relationship between the arches (maxillary and mandibular) returning the vertical dimension and replacing missing teeth. Complete denture; is the complete removable prosthesis muco supported for edentulous patients (total toothless). Partial dentures; is the removable prosthesis that replaces one or more teeth missing from a dental arch. <a id="

A crown, inlay or onlay is the prosthetic construction that is placed fixed in a previously prepared tooth whose objective is to cover the coronal part of the tooth when a pathology or accident occurs such as, and not limited to, dental caries that destroy great part of the tooth, fractures of cusps or endodontics treated tooth. The reason for the crown, inlay or onlay is to protect and restore the anatomy of the affected tooth. These restorations are often made of gold, different alliations of metals/porcelain or porcelain/ceramic. <a id="

Regional anesthesia is one that is selectively applied to a specific region of the body. Under the term of regional anesthesia is included: ü Spinal: It is produced by the injection of an anesthetic agent, under the spinal cord membrane. ü Epidural (Blocking): The anesthesia produced by the injection of an anesthetic agent between the vertebral spines and below the flavo ligament in the extradural space. ü Analgesia / neuraxial anesthesia: epidural anesthesia continues through a catheter into the epidural space. This modality is started during labor and continues until delivery or cesarean section. Normally the catheter is not changed in the case of caesarean section but if a higher concentration of the anesthetic agent is added. ü Nerve block: Infiltration around the nerve at the exit of the spine. (For example, a nerve plexus or an individual peripheral nerve can be blocked). ü Local infiltration: Infiltration in the area where the nerve ends. <a id="

There are numerous commercially available genetic and molecular diagnostic, prognostic, and therapeutic tests for individuals with certain diseases or asymptomatic individuals with future risk. This review relates to genetic and molecular diagnostic tests not addressed in a separate review and have not received clearance/approval/de novo classification from the Food and Drug Administration (FDA). If a separate evidence review exists, then conclusions reached there supersede conclusions here. The main criterion for inclusion in this review is the limited evidence on the clinical utility for the test. As these tests do not have clinical utility, the evidence is insufficient to determine that the technology results in an improvement in the net health outcome and will not be subjected to a full evidence review.

Multiple biomarkers are being evaluated to predict response to immunotherapy for individuals with cancer. Immune checkpoint inhibitors and associated companion diagnostic tests for these therapies have received U.S. Food and Drug Administration approval for cancer-specific and, more recently, tumor agnostic indications. Extensive evidence review is not included for somatic tests of individual genes (not gene panels) associated with U.S. Food and Drug Administration (FDA)-approved therapeutics (ie, as companion diagnostic tests) for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher. Pivotal evidence is included in Table 1 for informational purposes. Additionally, no evidence review is provided for somatic tests of individual genes that do not have associated FDA-approved therapies regardless of NCCN recommendations, as these off-label therapies are deemed investigational per the Blue Cross and Blue Shield Association Medical Policy Program Policies and Procedures.

Biomarker-targeted therapy has shown a clear survival benefit in patients with ovarian cancer. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA testing (also known as a liquid biopsy) is proposed as a non-invasive alternative.

Biomarker-targeted therapy has shown a clear survival benefit in individuals with metastatic prostate cancer. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA (ctDNA) (also known as liquid biopsy) is proposed as a non-invasive alternative.

Hereditary Diffuse Gastric Cancer (HDGC, sometimes called signet ring gastric cancer) is an autosomal dominant syndrome characterized by the development of diffuse gastric cancers. CDH1 is a tumor suppressing gene that encodes the cell-to-cell adhesion protein E-cadherin. Germline variants in the CDH1 gene have been associated with an increased risk of developing HDGC and lobular breast cancer. Testing for CTNNA1 variants has also been proposed for individuals with or at risk for HDGC. Knowledge of variant status in individuals at potentially increased risk may impact health care decisions to reduce risk.

This evidence review addresses the use of tumor-informed circulating tumor DNA (ctDNA) testing for cancer management. The purpose of tumor-informed ctDNA testing in individuals with cancer is to predict disease course to inform treatment decisions and to monitor for recurrence following treatment.

Multiple biomarkers are being evaluated to select treatment with an FDA-approved targeted treatments for patients with unresectable, recurrent, relapsed, refractory, advanced or metastatic cancer. These include tissue-based testing as well as circulating tumor DNA and circulating tumor cell testing (known as liquid biopsy). The objective of this evidence review is to examine whether genetic biomarker testing for BRCA1, BRCA2 , PIK3CA, ESR1, BRAF, EGFR, EZH2, HER2, FOLR1, FLT3, CLDN18, FGFR3, PDGFRA, TP53, KRAS, NRAS, IDH1, IDH2, HLA, KIT, MET, homologous recombination deficiency (HDR), and homologous recombination repair (HRR) gene variants, ALK, ROS1, RET, FGFR2, PDGFR, NTRK, Philadelphia chromosome rearrangements or fusions, and other molecular signatures, such as, PD-L1, MSI/MMR, and TMB status, in tumor tissue, or circulating tumor DNA improves the net health outcome in patients with unresectable, recurrent, relapsed, refractory, advanced or metastatic cancer who are considering targeted therapy (Table 1). Table PG1. Gene Variants Found in DNA for Targeted Therapy Biomarker Indication ALK rearrangements/fusions NSCLC ATM Prostate BRAF Breast, NSCLC, metastatic CRC, Melanoma, Glioma, and ATC BRCA1/2 Breast, Ovarian, Pancreatic, and Prostate CLDN18 Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma EGFR NSCLC, CRC, ERBB2 (HER2) Breast, NSCLC, Gastric and Gastroesophageal Cancer, and Biliary Tract Cancer (gallbladder adenocarcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma) ESR1 Breast EZH2 Follicular Lymphoma FGFR2 Cholangiocarcinoma FGFR3 Urothelial Cancer FLT3 (ITD/TDK) Acute Myelogenous Leukemia FOLR1 Epithelial Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer HER2 NSCLC and metastatic CRC HLA Uveal Melanoma HRDa Ovarian HRR (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) Prostate IDH1 Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Cholangiocarcinoma, Astrocytoma, Oligodendroglioma, and Glioma IDH2 Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Astrocytoma, Oligodendroglioma, and Glioma KIT Aggressive Systemic Mastocytosis KRAS NSCLC and metastatic CRC MET NSCLC MSI (MLH1, MSH2, MSH6, PMS1 and PMS2)/MMR (MLH1, MSH2, PMS2, and MSH6) Solid tumors Not MSI-H Endometrial Carcinoma NRAS metastatic CRC NTRK rearrangements/fusions Breast, NSCLC, metastatic CRC, Ovarian, Prostate, Melanoma, Glioma, and other solid tumors PDGFRA Gastrointestinal Stromal Tumors PDGFRB Myelodysplastic Syndrome/Myeloproliferative Disease PD-L1 Solid tumors PIK3CA Breast RET rearrangements/fusions Breast, NSCLC, metastatic CRC, Medullary Thyroid Cancer, Thyroid Cancer, and other solid tumors ROS1 rearrangements/fusions NSCLC TMB Solid tumors TP53 B-cell Chronic Lymphocytic Leukemia ATC: anaplastic thyroid cancer; CRC: colorectal cancer; HRD: homologous recombination deficiency; HRR: homologous recombination repair; NSCLC: non-small cell lung cancer; TMB: tumor mutational burden. a Genomic instability score

It is estimated that approximately 20% of women presenting for assessment for hereditary ovarian cancer (OC) risk have a variant in a gene that increases the risk of cancer. BRIP1, RAD51C, RAD51D, NBN, and mismatch repair genes are estimated to contribute to 10% of hereditary OC cases. Approximately 60% of the familial relative risk in OC is unexplained. Risk for BRIP1, RAD51C, RAD51D, and NBN carriers is increased approximately 3- to 19-fold, 3- to 6-fold, 5- to 12-fold, and 2- to 3.5-fold respectively. Risk estimates may be higher in patients with a family history of OC or a family history of a specific gene variant. Germline genetic testing for BRCA1, BRCA2, and PALB2 is addressed separately in evidence review 2.04.02. Germline genetic testing for ATM is addressed separately in evidence review 2.04.126.

Chronic migraine and severe headaches are common conditions and the available treatments are not universally effective. A proposed treatment option is blocking the sphenopalatine ganglion (SPG) nerve by applying topical anesthetic intranasally. Several catheters approved by the U.S. Food and Drug Administration are available for the SPG blocking procedure.

Acupuncture describes a group of procedures intended to stimulate anatomical points with the goal of precipitating physiologic changes. Acupuncture has been proposed to treat the pain of various etiologies as well as other non-pain disorders including the alleviation of opioid dependence withdrawal symptoms. This review addresses acupuncture for pain management, nausea and vomiting, and opioid dependence.

Measurable residual disease (MRD), also known as minimal residual disease, refers to residual clonal cells in blood or bone marrow following treatment for hematologic malignancies. MRD is typically assessed by flow cytometry (FC) or polymerase chain reaction, which can detect 1 clonal cell in 100,000 cells. It is proposed that next-generation sequencing (NGS), which can detect 1 residual clonal sequence out of 1,000,000 cells, will improve health outcomes in patients who have been treated for hematologic malignancies such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL).

HMG-CoA reductase inhibitors, or statins, which are widely used to treat hypercholesterolemia, can cause muscle-related adverse events. Serious myopathy (ie, myositis, rhabdomyolysis) can also occur and may be associated with variants in the SLCO1B1 gene. Commercially available tests for the presence of SLCO1B1 variants are marketed for use in predicting the risk of myopathy for patients taking statins.

Celiac disease (CD) is currently diagnosed by serology, medical history, and response to a gluten-free diet, with confirmation by small intestinal biopsy. Human leukocyte antigen (HLA) testing may be useful for ruling out disease in symptomatic patients when findings of other tests are inconclusive.

Biologic agents used to treat autoimmune diseases include infliximab, adalimumab, vedolizumab, and ustekinumab. Infliximab (Remicade) is an intravenous tumor necrosis factor α blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, Crohn disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. Adalimumab (Humira) is a subcutaneous tumor necrosis factor α inhibitor that is FDA approved for the treatment of rheumatoid arthritis, Crohn disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis in adults and those with juvenile idiopathic arthritis, hidradenitis suppurativa, and uveitis. Vedolizumab (Entyvio) is an intravenous integrin receptor antagonist that is FDA approved for the treatment of ulcerative colitis and Crohn disease in adults. Ustekinumab (Stelara) is an intravenous and subcutaneous human interleukin-12 and -23 antagonist that is FDA approved for the treatment of Crohn disease and ulcerative colitis in adults, and psoriatic arthritis and plaque psoriasis in children and adults. Following the primary response to these medications, some individuals become secondary nonresponders. The development of antidrug antibodies is considered a cause of this secondary nonresponse.

Pancreatic cancer is the fourth leading cause of cancer death in the United States, accounting for 8.3% of all cancer deaths in 2023. Multiple genetic syndromes are associated with an increased risk for pancreatic cancer, and approximately 10% to 15% of patients with pancreatic cancer are thought to have a hereditary susceptibility to the disease. Germline genetic testing for pancreatic cancer susceptibility genes is proposed to guide treatment decisions in patients with pancreatic cancer, and to inform decisions about surveillance in asymptomatic patients at high risk of pancreatic cancer.

Complete Appendix to Guidelines available at http://journals.aace.com. Endocr Pract. Apr 02 2017; 23(4): 479-497. PMID 28156151″>31, Guidance from NICE was also included in the review.32, The quality of the guidelines was assessed using the Appraisal of Guidelines for Research and Evaluation II instrument, with guideline quality ranging from average to good. Most guidelines agreed that genetic testing follows cholesterol testing, physical findings distinctive of FH, and highly suggestive family history of FH. Universal screening for FH was not recommended. This review highlighted the importance of genetic testing for FH in children, because aggressive treatment at an earlier age may prevent premature coronary heart disease.

Multiple myeloma is a genetically complex and invariably fatal disease. A host of well-characterized factors related to tumor biology, tumor burden, and patient-centered characteristics are used to stratify individuals into high-, intermediate-, and standard-risk categories for prognostic purposes, as well as determining treatment intensity. However, clinical outcomes have varied among individuals in the same risk category who received similar therapy. Thus, more specific methods have been sought to classify multiple myeloma; one such method being proposed is the utilization of a microarray-based gene expression profile (GEP) analysis, which serves to reveal the underlying activity of cellular biologic pathways. This method lends itself to a variety of benefits including the ability to risk-stratify individuals with multiple myeloma, as well as guide treatment decisions.

Lipoprotein(a) (LPA) is a lipid-rich particle similar to low-density lipoprotein and has been determined to be an independent risk factor for coronary artery disease. Patients with a positive test for the LPA genetic variant, rs3798220, have a higher risk for thrombosis and therefore may derive greater benefit from the antithrombotic properties of aspirin. As a result, testing for the rs3798220 variant has been proposed as a method of stratifying benefit from aspirin treatment. For individuals who have a high risk of thrombosis who receive genetic testing for LPA rs3798220 variant, the evidence includes observational studies. Relevant outcomes are test validity, medication use, and morbid events. The LPA minor allele, rs3798220, is associated with higher levels of LPA and a higher risk for cardiovascular events. This allele is infrequent in the population and is associated with a modest increase in cardiovascular risk in the general population. Testing for this allele is commercially available, but performance characteristics are uncertain, and standardization of testing has not been demonstrated. Several observational studies have reported that this variant is an independent risk factor for cardiovascular disease, but some studies have not reported a significant association. Evidence from a post hoc analysis of the Women’s Health Study reported that carriers of the allele might derive greater benefit from aspirin therapy compared with noncarriers. It is unclear whether this information, which derives from genetic testing, leads to changes in management; in particular, it cannot be determined from available evidence whether deviating from current guidelines on aspirin therapy based on LPA genetic testing improves outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Inherited retinal dystrophy can be caused by recessive variants in the RPE65 gene. Patients with biallelic variants have difficulty seeing in dim light and experience progressive loss of vision. These disorders are rare and have traditionally been considered untreatable. Gene therapy with an adeno-associated virus vector expressing RPE65 has been proposed as a treatment to improve visual function.

Neurofibromatoses are autosomal dominant genetic disorders associated with tumors of the peripheral and central nervous systems. There are 3 clinically and genetically distinct forms: neurofibromatosis (NF) type 1, NF type 2-related schwannomatosis (formerly NF type 2), and schwannomatosis. The potential benefit of genetic testing for NF type 1 (NF1), neurofibromatosis type 2 (NF2), or SPRED1 pathogenic variants is to confirm the diagnosis in an individual with suspected NF who does not fulfill clinical diagnostic criteria or to determine future risk of NF in asymptomatic at-risk relatives.

Alpha1-antitrypsin deficiency (AATD) is an autosomal recessive genetic disorder that results in decreased production of functional alpha1-antitrypsin (AAT) protein or production of abnormal types of the protein that are functionally deficient. Individuals with AATD, especially smokers, have an increased risk of lung and liver disease. Available tests measure serum AAT levels and phenotype AAT protein variants. Genetic testing is also available to detect the most common pathogenic variants associated with AATD.

Adolescent idiopathic scoliosis (AIS) is a disease of unknown etiology that causes mild-to-severe spinal deformity in approximately 1% to 3% of adolescents. While there is controversy about the value of screening and treatment, once diagnosed, patients are frequently closely followed. In cases with significant progression of curvature, both medical (bracing) and surgical (spinal fusion) interventions are considered. The ScoliScore AIS prognostic DNA-based test uses an algorithm incorporating results of testing for 53 single nucleotide variants (SNVs), along with the patient’s presenting spinal curve (Cobb angle), to generate a risk score (range, 1 to 200), which can be used qualitatively or quantitatively to predict the likelihood of spinal curve progression.

Several single nucleotide variants (SNVs), which are single base-pair variations in the DNA sequence of the genome, have been found to be associated with breast cancer, and are common in the population, but confer only small increases in risk. Commercially available assays test for several SNVs to predict an individual’s risk of breast cancer relative to the general population. Some of these tests incorporate clinical information into risk prediction algorithms. The intent of this type of test is to identify subjects at increased risk who may benefit from more intensive surveillance.

Laboratory tests have been developed that detect the expression of different genes in pigmented lesions or melanoma tumor tissue. Test results may help providers and patients decide whether to biopsy suspicious pigmented lesions, aid in the diagnosis of lesions with indeterminate histopathologic lesions or determine whether to perform sentinel lymph node biopsy in patients diagnosed with stage I or II cutaneous melanoma. This report summarizes the evidence of 3 tests.

There are numerous commercially available genetic and molecular diagnostic, prognostic, and therapeutic tests for individuals with certain diseases or asymptomatic individuals with future risk. This evidence review evaluates miscellaneous genetic and molecular diagnostic tests not addressed in a separate review. If a separate evidence review exists, then conclusions reached there supersede conclusions here. The main criterion for inclusion in this review is the limited evidence on the clinical validity for the test. As a result, these tests do not have clinical utility, and the evidence is insufficient to determine the effect on health outcomes.

Tamoxifen is prescribed as a component of adjuvant endocrine therapy to prevent endocrine receptor-positive breast cancer recurrence, to treat metastatic breast cancer, and to prevent disease in high-risk populations and in women with ductal carcinoma in situ. Tamoxifen is a pro-drug that undergoes extensive metabolism to yield its active form: 4-hydroxytamoxifen and endoxifen (primary active form) via the CYP2D6 enzyme. Variants in the CYP2D6 gene are associated with significant alterations in endoxifen concentrations leading to the hypothesis that CYP2D6 variation may affect the clinical outcomes of women treated with tamoxifen but not with drugs not metabolized by CYP2D6 such as anastrozole.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease (CTD) that can be difficult to diagnose because individuals often present with diverse, nonspecific symptoms that overlap with other CTDs; to further complicate matters, commonly used laboratory tests are not highly accurate. Moreover, similar symptoms may also present themselves in individuals with fibromyalgia. Currently, differential diagnosis depends on a combination of clinical signs and symptoms and individual laboratory tests. More accurate laboratory tests for SLE and other CTDs could facilitate the diagnosis of the disease. Laboratory-developed, diagnostic panel tests with proprietary algorithms and/or index scores for the diagnosis of SLE and other autoimmune CTDs are commercially available.

Mitochondrial diseases are multisystem diseases that arise from dysfunction in the mitochondrial protein complexes involved in oxidative metabolism. There are many related but distinct syndromes and some patients have overlapping syndromes. As a result, these disorders can be difficult to diagnose. Genetic testing has the potential to improve the accuracy of diagnosis for mitochondrial diseases. Genetic testing also has the potential to determine future risk of disease in individuals who have a close relative with a pathogenic variant. Diagnostic genetic testing for mitochondrial disorders and carrier testing of known familial variants associated with mitochondrial disorders is addressed in this review. Carrier screening for mitochondrial disorders associated with autosomal recessive inheritance of nuclear DNA variants is addressed in evidence review 11.003.048.

Proteogenomics refers to the integration of genomic information with proteomic and transcriptomic information to provide a more complete picture of genome function. The current focus of proteogenomics is primarily on the diagnostic, prognostic, and predictive potential of proteogenomics in various cancers. One commercial proteogenomic test is available, the GPS Cancer test.

Uveal melanoma is associated with a high rate of metastatic disease, and survival after the development of metastatic disease is poor. Prognosis following treatment of local disease can be assessed using various factors, including clinical and demographic markers, tumor stage, tumor characteristics, and tumor cytogenetics. Gene expression profiling (GEP) can be used to determine prognosis, and gene expression profile testing is commercially available.

Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in peripheral blood, referred to as "liquid biopsy," have several potential uses for guiding therapeutic decisions in patients with cancer or being screened for cancer. This evidence review evaluates uses for liquid biopsies not addressed in a separate review. If a separate evidence review exists, then conclusions reached there supersede conclusions here.

Clinical assessment and noninvasive imaging of chronic heart failure can be limited in accurately diagnosing patients with heart failure because symptoms and signs can poorly correlate with objective methods of assessing cardiac dysfunction. For management of heart failure, clinical signs and symptoms (eg, shortness of breath) are relatively crude markers of decompensation and occur late in the course of an exacerbation. Thus, circulating biomarkers have potential benefit in heart failure diagnosis and management. A protein biomarker, soluble suppression of tumorigenicity-2 (sST2), has elicited interest as a potential aid to predict risk and manage therapy of heart failure as well as to manage in patients in the setting of heart transplant. For individuals who have chronic heart failure who receive the sST2 assay to determine prognosis and/or to guide management, the evidence includes correlational studies and 2 meta-analyses. Relevant outcomes are overall survival, quality of life, and hospitalization. Most of the evidence is from reanalysis of existing randomized controlled trials and not from studies specifically designed to evaluate the predictive accuracy of sST2, and prospective and retrospective cross-sectional studies made up a large part of 1 meta-analysis. Studies have mainly found that elevated sST2 levels are statistically associated with elevated risk of mortality. A pooled analysis of study results found that sST2 significantly predicted overall mortality and cardiovascular mortality. Several studies, however, found that sST2 test results did not provide additional prognostic information compared with N-terminal pro B-type natriuretic peptide levels. Moreover, no comparative studies were identified on the use of the sST2 assay to guide management of patients diagnosed with chronic heart failure. The evidence is insufficient to determine the effects of the technology on health outcomes. For individuals who have heart transplantation who receive sST2 assay to determine prognosis and/or to predict acute cellular rejection, the evidence includes a small number of retrospective observational studies on the Presage ST2 Assay. Relevant outcomes are overall survival, morbid events, and hospitalization. No prospective studies were identified that provide high-quality evidence on the ability of sST2 to predict transplant outcomes. One retrospective study (n = 241) found that sST2 levels were associated with acute cellular rejection and mortality; another study (n = 26) found that sST2 levels were higher during an acute rejection episode than before rejection. The evidence is insufficient to determine the effects of the technology on health outcomes. For individuals who have heart transplantation who receive myTAIHEART assay to determine acute cellular rejection, the evidence includes observational studies. A validation study using 158 matched endomyocardial biopsy-plasma pairs from 76 pediatric and adult heart transplant recipients (ages 2 months or older, and 8 days more post-transplant) found a donor-specific fraction cutoff (0.32%) that produced a 100% negative predictive value for Grade 2 or higher acute cellular rejection. A prospective observational blinded study (n=174; pediatric=101, adult=73) using biopsy-paired samples found that myTAIHEART level was associated with acute cellular and antibody-mediated rejection in both adult and pediatric heart transplant populations, and that an optimal donor fraction threshold (0.3%) ruled out the presence of either acute cellular rejection or antibody-mediated rejection. Both studies received industry funding. The evidence is insufficient to determine the effects of the technology on health outcomes.

Plasma-based proteomic screening and gene expression profiling of bronchial brushing are molecular tests available in the diagnostic workup of pulmonary nodules. To rule out malignancy, invasive diagnostic procedures such as computed tomography-guided biopsies, bronchoscopies, or video-assisted thoracoscopic procedures are often required, but each carry procedure-related complications ranging from postprocedure pain to pneumothorax. Molecular diagnostic tests have been proposed to aid in risk-stratifying patients to eliminate or necessitate the need for subsequent invasive diagnostic procedures.

Genetic testing to determine kinesin-like protein 6 (KIF6) Trp719Arg variant status is being evaluated as a test to predict the risk of future cardiovascular events and as a test to predict response to statin therapy, particularly in high-risk patients. For individuals who are asymptomatic with risk of cardiovascular disease and undergoing treatment with statin therapy who receive testing for KIF6 Trp719Arg variant status, the evidence includes secondary analyses of randomized controlled trials, case-control studies, and a quasi-experimental single-arm study. Relevant outcomes are overall survival, test accuracy and validity, change in disease status, morbid events, and medication use. Data supporting the association between KIF6 variant status and coronary artery disease outcomes are contradictory. The most recent evidence from large populations with different vascular disease risk levels has not supported a significant association between coronary artery disease risk and the presence of the variant. Further, studies of the association between response to statin therapy and KIF6 variant status are mixed. However, a large meta-analysis has shown that carriers of the KIF6 variant derive greater clinical benefit from low-density lipoprotein cholesterol reduction (a 13% reduction in the risk of coronary artery disease outcomes) compared with noncarriers. Currently, no prospective randomized controlled trials have evaluated the impact of testing for KIF6 variants on changes in clinical management (eg, intensifying the statin treatment in carriers, use of alternative approaches for lipid management in noncarriers) or outcomes. One nonrandomized study has suggested that subjects with KIF6 genotype results showed greater adherence to statin therapy, but, overall, it is uncertain whether testing for KIF 6 variants will alter the clinical management decisions. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Dilated cardiomyopathy (DCM) is characterized by progressive left ventricular enlargement and systolic dysfunction, leading to clinical manifestations of heart failure. There are a variety of causes of DCM, including genetic and nongenetic conditions. Genetic forms of DCM are heterogeneous in their molecular basis and clinical expression. Genetic testing for DCM has potential utility for confirming a diagnosis of genetic DCM and as a prognostic test in family members when familial DCM is present.

CHARGE syndrome is a rare genetic condition associated with multiple congenital anomalies. In many individuals, the diagnosis can be made based on clinical findings. However, the phenotype of the disease is highly variable, and some patients do not fulfill the criteria for a definitive diagnosis by clinical findings. Sequence analysis of the CHD7 gene detects variants in most individuals with CHARGE syndrome.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease that typically presents before the age of 20 years with the weakness of the facial muscles and the scapular stabilizer muscles. The usual clinical course is a slowly progressive weakness, although the severity is highly variable, and atypical presentations occur. Genetic testing for FSHD has been evaluated as a tool to confirm the diagnosis.

Age-related macular degeneration is a complex disease involving both genetic and environmental influences. Testing for variants at certain genetic loci has been proposed to predict the risk of developing advanced age-related macular degeneration. Age-related macular degeneration is divided into the dry form, associated with slowly progressive vision loss, and the wet form, which may be associated with rapidly progressive and severe vision loss. The risks of age-related macular degeneration and of developing the wet form are associated with genetic and nongenetic (eg, age, smoking) factors.

Invasive prenatal (fetal) diagnostic testing may be used to identify pathogenic genetic alterations in fetuses at increased risk based on prenatal screening or in women who choose to undergo diagnostic testing due to other risk factors. This evidence review only addresses the use of chromosomal microarray (CMA) testing, molecular diagnosis of single-gene disorders, and next-generation sequencing.

National guidelines recommend that all pregnant individuals be offered screening for fetal chromosomal abnormalities, most of which are aneuploidies, an abnormal number of chromosomes. Trisomy syndromes are aneuploidies involving 3 copies of 1 chromosome. Trisomies 21, 18, and 13 are the most common forms of fetal aneuploidy that survive to birth. There are numerous limitations to standard screening for these disorders using the maternal serum and fetal ultrasound. Noninvasive prenatal screening analyzing fetal cell-free DNA (cfDNA) in maternal serum is a potential complement or alternative to conventional serum screening. Noninvasive prenatal screening (NIPS) using cell-free fetal DNA has also been proposed to screen for microdeletions. Prenatal testing for twin zygosity using fetal cfDNA has been proposed to inform decisions about early surveillance for twin-twin transfusion syndrome and other monochorionic twin-related abnormalities.

Assessment of disease activity in rheumatoid arthritis (RA) is an important component of management with a goal of treatment to maintain low disease activity or achieve remission. There are a variety of instruments for measuring RA disease activity. The instruments use combinations of physical exam findings, radiologic results, and serum biomarkers to construct a disease activity score. A multibiomarker disease activity (MBDA) instrument is a disease activity measure that is comprised entirely of serum biomarkers. The Vectra test is a commercially available MBDA blood test that measures 12 biomarkers to construct a disease activity score. Concentrations of these 12 biomarkers are entered into a proprietary formula which, after adjustment by age, gender, and adiposity ( ie, leptin) levels, generates a disease activity score ("adjusted MBDA score") that ranges from 1 (low disease activity) to 100 (high disease activity).

Proteomic testing has been proposed as a way to predict survival outcomes, as well as the response to and selection of targeted therapy for patients with non-small-cell lung cancer (NSCLC). One commercially available test (the VeriStrat assay) has been investigated as a predictive marker for response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

Variability in systemic exposure to 5-fluorouracil chemotherapy is thought to directly impact 5-fluorouracil tolerability and efficacy. The standard approach is dosing according to body surface area. Two alternative approaches have been proposed for modifying use of 5-fluorouracil: (1) dosing based on the determined area under the curve serum concentration target and (2) genetic testing for variants affecting 5-fluorouracil metabolism. For genetic testing, currently available polymerase chain reaction tests assess specific variants in genes encoding dihydropyrimidine reductase (DPYD) and thymidylate synthase (TYMS) in the catabolic and anabolic pathways of 5-fluorouracil metabolism, respectively.

Marfan syndrome (MFS) is a systemic connective tissue disease (CTD) with a high degree of clinical variability and phenotypes overlapping with other syndromes and disorders. The diagnosis of most suspected CTDs can be based on clinical findings and family history. Some of these disorders are associated with a predisposition to the development of progressive thoracic aortic aneurysms and dissection. Accurate diagnosis of 1 of these syndromes can lead to changes in clinical management, including surveillance of the aorta, and surgical repair of the aorta, when necessary, as well as surveillance for multisystem involvement in syndromic forms of thoracic aortic aneurysms and dissection. Known pathogenic variants are associated with MFS and the other connective tissue disorders that share clinical features with MFS.

Preimplantation genetic testing involves the analysis of biopsied cells as part of an assisted reproductive procedure. It is generally considered to be divided into 2 categories. Preimplantation genetic diagnosis is used to detect a specific inherited disorder in conjunction with in vitro fertilization (IVF) and aims to prevent the birth of affected children to couples at high-risk of transmitting a disorder. Preimplantation genetic screening may also involve testing for potential genetic abnormalities in conjunction with IVF for couples without a specific known inherited disorder.

Testing for O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation has been proposed as a method to predict which patients with malignant gliomas may benefit from the use of alkylating agent chemotherapy, such as temozolomide (TMZ). Malignant gliomas are often treated with combined therapy, including resection, chemotherapy, and radiotherapy. However, combined therapy may be too intense in the elderly population, in whom these tumors are most commonly seen. The following conclusions are based on a review of the evidence, including but not limited to published evidence and clinical expert opinion, solicited via BCBSA's Clinical Input Process. For individuals who have high-grade glioma(s) who receive MGMT promoter methylation testing, the evidence includes cohort studies of prognosis, studies nested within randomized trials, and treatment trials that selected subjects based on MGMT methylation status. Relevant outcomes include overall survival, disease-specific survival, test accuracy, and changes in disease status. While there are no studies directly evaluating whether the use of MGMT methylation testing improves patient outcomes, MGMT status is consistently associated with outcomes of glioma patients. Data from randomized controlled trials have shown that MGMT promoter methylation is predictive for response to alkylating chemotherapeutic agents such as TMZ. The response rate and overall survival with the use of TMZ are higher in patients who have MGMT promoter methylation. While TMZ offers some benefit regardless of MGMT methylation status, studies have consistently suggested that MGMT methylation identifies patients who are more likely to benefit from TMZ. TMZ combined with radiotherapy remains the standard of care for most patients. TMZ is associated with a modest increase in hematologic adverse events compared with radiotherapy alone. Counseling about risks and benefits in a patient with comorbidities may result in a choice to avoid TMZ when that patient is less likely to benefit from the treatment. The published evidence supports a meaningful improvement in the net health outcome. Evidence reported through clinical input further supports that this use provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice. Patient selection criteria for MGMTgene promoter from glioma tumor tissue include the following criteria: (1) have a tumor type consistent with high-­grade malignant glioma (eg, glioblastoma multiforme, anaplastic astrocytoma); and (2) candidate for temozolomide therapy or radiotherapy; and (3) methylation results will be used to direct therapy choices. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

The inherited peripheral neuropathies are a heterogeneous group of diseases that may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner. These diseases can generally be diagnosed based on clinical presentation, nerve conduction studies, and family history. Genetic testing has been used to diagnose specific inherited peripheral neuropathies.

Using information about an individual's genotype may help in guiding warfarin dosing and could reduce the time to dose stabilization and selection of an appropriate maintenance dose that might avoid the consequences of too much or too little anticoagulation.

Variants in the Duchenne muscular dystrophy (DMD) gene, which encodes the protein dystrophin, may result in a spectrum of X-linked muscle diseases, including the progressive diseases Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) and dilated cardiomyopathy. Genetic testing can confirm a diagnosis of a dystrophinopathy and distinguish the less from more severe forms, as well as identify female carriers at risk.

Commercially available cancer susceptibility gene panels can test for multiple variants associated with a specific type of cancer or can include variants associated with a wide variety of cancers. Some of these variants are associated with inherited cancer syndromes. The cancer type(s), as well as a cancer history involving multiple family members, increase the clinical concern for the presence of a heritable genetic variant. It has been proposed that variant testing using next-generation sequencing (NGS) technology to analyze multiple genes at once (panel testing) can optimize genetic testing in these individuals compared with sequencing single genes.

In the treatment of Philadelphia chromosome-positive leukemias, various nucleic acid-based laboratory methods may be used to detect the BCR-ABL1 fusion gene for confirmation of the diagnosis; for quantifying mRNA BCR-ABL1 transcripts during and after treatment to monitor disease progression or remission; and for identification of ABL kinase domain (KD) single nucleotide variants related to drug resistance when there is inadequate response or loss of response to tyrosine kinase inhibitors (TKIs), or disease progression.

Commercially available genetic tests can perform a host of functions, such as providing a guided intervention in both symptomatic or asymptomatic people, identifying people at risk for future disorders, predicting the prognosis of a diagnosed disease, and predicting the appropriate treatment response. The conceptual framework provided herein offers an outline for evaluating the utility of genetic tests, by classifying the types of genetic tests into clinically relevant categories and developing criteria that can be used for evaluating tests in each category. This conceptual framework addresses genetic testing in nonreproductive settings. Genetic testing in reproductive settings is addressed separately (eg, evidence reviews 2.04.107, 2.04.116, 4.02.05). For categories of genetic testing for which the benefit of testing is the individual, criteria for medical necessity apply. When the benefit of testing is not for the individual, but for a family member, medical necessity criteria may not apply, and the criteria are developed for clinical utility.

Treatment of acute myeloid leukemia (AML) is based on risk stratification, primarily related to age and tumor cytogenetics. In individuals with cytogenetically normal AML, the identification of variants in several genes, including FLT3, NPM1, and CEBPA, has been proposed to allow for further segregation in the management of this heterogeneous disease.

Fanconi anemia (FA) is an inherited disorder characterized by congenital abnormalities, bone marrow failure, and predisposition to hematologic malignancies. The disease is associated with early mortality and a high degree of morbidity for affected individuals. The potential utility of genetic testing is in confirming the diagnosis in cases that are inconclusive after standard workup, in testing asymptomatic individuals for future risk of disease, in carrier testing for individuals at increased risk for the variant, and in the prenatal testing of a fetus that has a high-risk for the disorder.

Alpha-thalassemia represents a group of clinical syndromes of varying severity characterized by hemolytic anemia and ineffective hematopoiesis. Genetic defects in any or all of 4 α-globin genes are causative of these syndromes. Rates of variants in the α-thalassemia gene vary across ethnic groups and are highest in individuals from Southeast Asia, Africa, and the Mediterranean region.

Whole exome sequencing (WES) sequences the portion of the genome that contains protein-coding DNA, while whole genome sequencing (WGS) sequences both coding and noncoding regions of the genome. Whole exome sequencing and WGS have been proposed for use in patients presenting with disorders and anomalies not explained by a standard clinical workup. Potential candidates for WES and WGS include patients who present with a broad spectrum of suspected genetic conditions.

To determine which patients need thyroid resection, many physicians will perform a cytologic examination of fine needle aspirate (FNA) samples from a thyroid lesion; however, this method has diagnostic limitations. As a result, assays using molecular markers have been developed to improve the accuracy of thyroid FNA biopsies.

Gene expression profile analysis and protein biomarkers have been proposed as a means to risk-stratify individuals with prostate cancer to guide treatment decisions. These tests are intended to be used either on prostate needle biopsy tissue to guide management decisions for active surveillance or therapeutic intervention, to guide radiotherapy use after radical prostatectomy (RP), or to guide medication selection after progression in metastatic castration-resistant prostate cancer.

Epilepsy is a disorder characterized by unprovoked seizures. It is a heterogeneous condition that encompasses many types of seizures and varies in age of onset and severity. Many genetic epilepsies are thought to have a complex, multifactorial genetic basis. There are also numerous rare epileptic syndromes associated with global developmental delay and/or cognitive impairment that occur in infancy or early childhood, and that may be caused by a single-gene pathogenic variant. Genetic testing is commercially available for a large number of genes that may be related to epilepsy.

Individual genes have been shown to be associated with the risk of psychiatric disorders and specific aspects of psychiatric drug treatment such as drug metabolism, treatment response, and risk of adverse events. Commercially available testing panels include several of these genes and are intended to aid in the diagnosis and management of mental health disorders.

Carrier screening is performed to identify individuals at risk of having offspring with inherited recessive single-gene disorders. Carriers are usually not at risk of developing the disease but can pass pathogenic variants to their offspring. Carrier testing may be performed in the prenatal or preconception periods.

Cancers of unknown primary represent 3% to 4% of cancers diagnosed in the United States. These cancers are heterogeneous and many accompanied by poor prognoses. A detailed history and physical combined with imaging and tissue pathology can identify some, but not all, primary sources of secondary tumors. It is suggested that identifying the likely primary source with gene expression profiling to direct treatment may improve health outcomes.

Fragile X syndrome (FXS) is the most common inherited form of mental disability and a known genetic cause of autism. The diagnosis is made with a genetic test that determines the number of CGG repeats in the fragile X mental retardation 1 gene (FMR1). FMR1 variant testing has been investigated in a variety of clinical settings, including the evaluation of individuals with a personal or family history of intellectual disability, developmental delay, or autism spectrum disorder and in reproductive decision-making in individuals with known FMR1 variants or positive cytogenetic fragile X testing. FMR1 variants also cause premature ovarian failure and a neurologic disease called fragile X-associated ataxia or tremor syndrome.

Genetic testing is available for individuals suspected of having cardiac ion channelopathies, including long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), and short QT syndrome (SQTS). These disorders are clinically heterogeneous and may range from asymptomatic to presenting with sudden cardiac death (SCD). Testing for variants associated with these channelopathies may assist in diagnosis, risk-stratify prognosis, and/or identify susceptibility for the disorders in asymptomatic family members.

Alzheimer disease (AD) is the most common cause of dementia in elderly patients. For late-onset AD, there is a component of risk that runs in families, suggesting the contribution of genetic factors. Early-onset AD is much less common but can occur in non-elderly individuals. Early-onset AD has a stronger component of family risk, with clustering in families, thus suggesting an inherited genetic disease-causing variant.

Numerous lipid and non-lipid biomarkers have been proposed as potential risk markers for cardiovascular disease (CVD). Biomarkers assessed herein include apolipoprotein B, apolipoprotein AI, apolipoprotein E, B-type natriuretic peptide, cystatin C, fibrinogen, high-density lipoprotein subclass, leptin, low-density lipoprotein subclass, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2). These biomarkers have been studied as alternatives or additions to standard lipid panels for risk stratification in CVD or as treatment targets for lipid-lowering therapy. Cardiovascular risk panels refer to different combinations of cardiac markers that are intended to evaluate the risk of CVD. There are numerous commercially available risk panels that include different combinations of lipids, noncardiac biomarkers, measures of inflammation, metabolic parameters, and/or genetic markers. Risk panels report the results of multiple individual tests, as distinguished from quantitative risk scores that combine the results of multiple markers into a single score.

Cutaneous melanoma is the third most common type of skin cancer, but the most lethal. Some cases of cutaneous malignant melanoma are familial. Potential genetic markers for this disease are being evaluated in affected individuals with a family history of the disease and in unaffected individuals in a high-risk family.

Laboratory tests have been developed to detect the expression, via messenger RNA, of different genes in breast tumor tissue and combine the results to determine prognosis in patients with breast cancer. Test results may help providers and patients decide whether to include adjuvant chemotherapy in the postsurgical management of breast cancer, to alter treatment in patients with ductal carcinoma in situ or triple-negative (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) breast cancer (TNBC), or to recommend extended endocrine therapy in patients who are recurrence-free at 5 years. This report summarizes the evidence for 6 tests and is organized by indication. For all tests and all indications, relevant outcomes include disease-specific survival and changes in disease status.

Various genetic and protein biomarkers are associated with prostate cancer. These tests have the potential to improve the accuracy of differentiating between which men should undergo prostate biopsy and which rebiopsy after a prior negative biopsy. This evidence review addresses these types of tests for cancer risk assessment. Testing to determine cancer aggressiveness after a tissue diagnosis of cancer is addressed in evidence review 2.04.111. Magnetic resonance imaging-targeted biopsy of suspicious lesions is assessed in evidence review 7.01.152.

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Hereditary hemochromatosis (HH), a common genetic disorder of iron metabolism, can lead to inappropriate iron absorption, toxic accumulation of iron, and organ damage. Genetic testing is available to assess variants in the human hemochromatosis (HFE) gene, which is responsible for most clinically significant cases of HH.

Hereditary breast and ovarian cancer syndrome describes the familial cancer syndromes related to variants in the BRCA genes (BRCA1 located on chromosome 17q21, BRCA2 located on chromosome 13q12-13). The PALB2 gene is located at 16p12.2 and has 13 exons. PALB2 protein assists BRCA2 in DNA repair and tumor suppression. Families with hereditary breast and ovarian cancer syndrome have an increased susceptibility to the following types of cancer: breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, ovarian cancer (at any age), cancer of the fallopian tube, primary peritoneal cancer, prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer.

In summary, the available literature regarding ductal lavage and suction collection systems for breast cancer risk assessment are inadequate to draw clinical conclusions. The policy statement remains unchanged. These procedures are investigational for the assessment of breast cancer risk given the insufficient evidence to evaluate the impact on net health outcome.Various collection systems have been investigated as techniques to obtain epithelial cells for cytological examination. These techniques have been evaluated as a diagnostic and risk assessment tool in patients at high risk of breast cancer. <a id="

Genetic testing is available for both those with and those at risk for various types of hereditary cancer. This review evaluates genetic testing for hereditary colorectal cancer (CRC) and polyposis syndromes, including familial adenomatous polyposis (FAP), Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer), MUTYH-associated polyposis (MAP), Lynch syndrome-related endometrial cancer, juvenile polyposis syndrome (JPS), and Peutz-Jeghers syndrome (PJS).

It is estimated that 3% to 5% of women presenting for assessment for hereditary breast/ovarian cancer risk have a variant in a gene that moderately increases the risk of cancer. CHEK2, ATM, and BARD1 variants are considered to be of moderate penetrance. Female carriers of CHEK2, ATM, and BARD1 have an approximately 2- to 4-fold increased risk of developing breast cancer compared with the general population. Risk estimates may be higher in patients with a family history of breast cancer or a family history of a specific variant.