Table 1.
Genetic categories
| Genetic categorya | Definition | Proposed clinical use example |
|---|---|---|
| Disease defining/diagnostic | Genetic variation associated with high likelihood of disease manifestation (high penetrance), usually in a dominant or recessive manner. For symptomatic individuals these variants may explain the cause of their disease. Individuals may be asymptomatic at the time of testing depending on age-related disease onset. Family member testing may be warranted to identify other at risk family members. | A patient presents with hypertrophic cardiomyopathy. A genetic cardiac panel is ordered and a pathogenic cardiomyopathy variant is identified. The overall test result, laboratory report, structured variant data, and associated interpretations are placed in the EHR’s genetic summary screen. An alert is sent to the ordering clinician indicating the result is available. The ordering geneticist reviews the report and determines that it is appropriate to add “Genetic Predisposition to Cardiomyopathy” to the patient’s problem list. The clinician establishes a plan for monitoring the patient. In addition, the clinician generates material the patient can use to contact other family members so they can consider testing. |
| Risk actionable | Genetic information that is medically actionable and should trigger a change to medical care (including treatment, surveillance, or avoiding agents). Most variants in this category are associated with a significant risk of morbidity and/or mortality (e.g., cancer, sudden cardiac death) and are relevant to family members. | A 29-year-old woman with no history of cancer has exome sequencing, and a known deleterious truncating mutation is identified in BRCA1. After consultation with a cancer geneticist, hereditary breast ovarian cancer syndrome is placed on the problem list and appropriate surveillance, including prophylactic surgery, is discussed. A careful family history indicates that more distant female relatives on the paternal side had early breast cancer. Follow-up genetic testing identifies presence of the BRCA1 mutation in her paternal aunt, but not in her 2 adult sisters. |
| Low risk not actionable, theoretically actionable | Genetic variants with modest effect sizes, low penetrance, and/or unclear functional implications. Some may be associated with intermediate endpoints (e.g., lipid levels) as opposed to discrete clinical endpoints; may also include simple nucleotide polymorphisms (SNPs) from genome-wide association studies as well as aggregated risk scores of such variants. These results maybe reported by some exome sequencing laboratories or genotyped as part of a gene panel (e.g., thrombophilia) or in support of research interests (e.g., cardiovascular risk scores). | A patient's exome is sequenced and variants in several candidate genes related to lipid metabolism and cardiometabolic disease are identified and reported in the EHR laboratory result section. These variants are aggregated into a risk score which suggest a 1.5-fold increase in risk of myocardial infarction. The physician is likely to follow American Heart Association (AHA) and other professional organization recommendations for inclusion of these results in clinical management. |
| Large chromosomal changes and cytogenetic test results | Copy number variants (deletions and duplications) and large structural rearrangements (inversions and translocations) that are detectable by standard karyotyping and/or chromosomal microarray. At present these are poorly characterized using exome sequencing approaches but are reported from whole genome analyses. | A male infant is born with multiple congenital anomalies and physical features suggestive of Down syndrome. A peripheral blood karyotype reveals trisomy 21 due to a Robertsonian translocation involving chromosomes 14 and 21 (46,XY rob(14;21)). The result is placed in the laboratory report section and the diagnosis of Down syndrome is placed on the Problem List. Parental testing is recommended. The infant’s mother is found to carry the translocation although this result is likely to appear in a separate EHR of the mother (also the normal result of the father). Appropriate genetic counseling for recurrence risk is provided. |
| Pharmacogenomics | Genetic variants that affect an individual’s ability to respond to drug therapy. Pharmacogenomic variants may alter therapeutic efficacy (e.g., whether or not a given drug will “work” for a patient) or safety (e.g., hypersensitivity reactions, changes to dose or drug selection). | A patient experiences an acute coronary syndrome and is prescribed clopidogrel to inhibit platelet aggregation. Clopidogrel is activated by the CYP2C19 enzyme which is encoded by the CYP2C19 gene. Several common CYP2C19 loss-of-function alleles are associated with higher risk of major adverse cardiovascular events in patients treated with clopidogrel. At the time the prescription is written a clinical decision support alert prompts the clinician to order CYP2C19 testing to help predict therapeutic response. The patient is found to be a CYP2C19 “poor metabolizer.” An alternative drug therapy is recommended based on the test results. |
| Carrier recessive | Genetic variants that are disease causing only if a patient carries 2 deleterious mutations in the same gene, but for which the patient only has one copy. These may be important for reproductive decision making but usually do not directly influence the patient’s health. | An individual undergoes exome testing and is found to be heterozygous for one CFTR mutation. The laboratory result is noted in the EHR and flagged as carrier status results. There is no information about her partner’s CFTR status in the patient’s EHR. |
| Somatic/tumor genetics | Knowledge of somatic alterations in tumor specimens may have immediate therapeutic implications with regard to US Food and Drug Administration (FDA) approval of targeted agents. In addition, mutations in pathways maybe suggestive of therapeutic efficacy. However, many oncologists may not be aware of how these mutations fit along pathway-specific therapeutic modules. Ongoing research is underway to determine how somatic mutations may impact treatment outcome for cancer patients. Thus, EHR representation of these tumor-specific mutations is important for ongoing improvement in cancer treatment. | A patient has a panel of multiple genes sequenced in her colon tumor. Analysis reveals a somatic mutation in KRAS codon 12 and a novel PIK3CA mutation in a codon where other mutations are know to cause PIK3CA activation. KRAS mutations are associated with lack of response to therapies that target the Epidermal Growth Factor (EGF) receptor in colon cancer patients. Activating mutations in PIK3CA have been associated with responsiveness to aspirin therapy. These findings are reported in EHR in a way that facilitates clinician access to decision support on how these classes of mutations may alter cancer care. |
| Incidental | Clinically significant genetic findings that are unrelated to the medical condition for which the genetic sequencing test was ordered. | A cancer risk panel of 40 genes is ordered for a male patient with a personal history of colon cancer. The patient is found to have a BRCA2 truncating mutation. The result is reported in the EHR and to the clinician as an incidental finding. There is a mechanism to alert the clinician about additional, unexpected follow up that may be necessary such as genetic counseling counseled about increased cancer risk and appropriate evaluation of family members. |
| Variants of uncertain significance (VUS) | Genetic variants that cannot be classified definitively as pathogenic or benign at this time. Many are missense sequence variants that alter a single amino acid or in noncoding portions of genes. Many VUS are previously undescribed novel variants. VUS are reported on a variety of genetic testing platforms. Over time, VUS may be reclassified as benign or pathogenic; however, laboratories differ in whether VUS results are amended on clinical reports. | A 43-year-old female patient with a personal and family history of breast cancer undergoes sequencing analysis of BRCA1 and BRCA2. A missense VUS is reported in BRCA1 and reported as a VUS. Therefore it is not recommended that testing for this variant be used to determine risk in relatives of this patient. Nine months later, a revised laboratory report reclassifies the variant as pathogenic based on additional evidence. The EHR is updated to now follow the recommendations found in Diagnostic and Actionable categories. |
| Uninterpreted variants | Genetic sequence variation in an individual that differs from the reference genome for which no analysis is performed to determine clinical significance. Large-scale genomic analysis will reveal many thousands of sequence variants, many of which are intergenic (that is not within known genes), or in genes with no known clinical relevance. Genomic testing laboratories have different policies about whether this information is included in laboratory reports or the EHR. | An individual with a progressively debilitating neuromuscular disorder of unknown diagnosis undergoes whole exome sequencing. A diagnostic finding in the GCH1 gene (nonsense mutation) is identified and reported in the EHR as consistent with a diagnosis of dopa-responsive dystonia. The detailed whole exome sequencing (WES) report also indicates that 77 055 sequence variants (including 17 299 coding variants) were detected but the policy of the testing laboratory is not to include the detailed genomic information in the EHR. The laboratory retains this information for potential re-analysis for 7 years in accordance with state requirements. |
| Newborn Screening | Newborn screening is a public health program designed to facilitate the prevention of developmental impairments, delayed physical growth, severe illness, and death through early detection and intervention of a select group of conditions | Newborn screening is performed on an infant to detect his risk for the conditions screened for in his state. Upon entering results of all of the screening tests into the newborn screening (NBS) state program laboratory information management system, the NBS laboratory professional is alerted that a confirmatory test needs to be run for one test [phenylketonuria (PKU)]. The reasoning for the recommendation, a “borderline abnormal” result, is displayed in the alert message. The NBS program sends the results to the EHR of the physician of record and the birthing hospital and initiates phone contact with the health professionals and family to communicate the need for a repeat test. The repeat test is obtained and the phenylalanine level is elevated confirming the diagnosis of PKU. The result is entered into the state newborn screening database and the result is sent to the EHR of the ordering physician for review. The state Newborn Screening program follows up by phone with the family and provider to insure that the infant has been referred to an accredited metabolic center. The report is placed in the genetic results section of the laboratory tab in the EHR. The diagnosis of PKU is placed on the problem list. |
| Sensitive genetic information | Genetic information that patients have decided they do not want their providers to know about, or that they do not want to know about themselves, such as Huntington’s disease risk, Alzheimer’s disease risk, prenatal testing, or cancer risk. Genetic results in this category may also belong in other categories | A patient has his exome sequenced, but chooses not to know his APOE results because of concerns about Alzheimer’s risk information. These results are not reported to the requesting hospital or displayed in his medical record; when his physician searches for them in the EHR she finds a note in the advanced directives tab that the patient’s preference is to not know the results for this genetic locus. |
aGenetic categories were designed to illustrate clinical or public health use cases and are not exclusive. Genetic results may fit multiple categories, e.g. sensitive – diagnostic results; actionable – incidental findings, etc,and some categories are clinical context dependent.