Suzanne M. Mahon

Purpose: Germline biomarker testing to assess inherited risk for developing malignancy has evolved quickly from testing for 1 or 2 genes from a few laboratories to ordering panels of 80 or more genes available from multiple laboratories. Many health professionals did not receive foundational information in training yet are expected to identify and manage care for individuals and families with germline risk. Errors in testing do occur and can have significant adverse consequences including missed opportunities for prevention and detection for the patient and family, unnecessary risk-reducing surgery, and even death. By better understanding these errors and underlying causes, as well as the potential negative consequences due to these errors, strategies can be developed to help prevent future harm to patients. Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting system a literature review was completed to identify case reports of errors in germline testing for hereditary cancer. Ovid MEDLINE, Scopus, and EBSCOHOST CINAHL, were searched from January 2009 through February 2025. Reference lists were reviewed to identify additional case reports. Each case report was abstracted to identify error(s), consequence(s), and potential error(s) prevented. Results: A total of 106 cases were identified from the search of the databases and 1 case using archival methods. Sixty-six (61%) cases described more than one error and 61 (44%) described more than one negative consequence. In 48 (45%) cases one or more additional errors were prevented when a genetics professional was consulted. The most common errors were misinterpretation of data, failure to take a full family history and review previous test results, not recognizing a syndrome, and selecting the wrong test or wrong laboratory for testing. Negative consequences included missed opportunities for prevention and detection for the patient and potentially other family members, one or more unnecessary risk-reducing surgeries in 10 patients, late detection of malignancy in 8 patients, and 7 patient deaths. Discussion: Although germline testing seems to be a simple laboratory test, many errors occur that have avoidable adverse consequences for both the patient and family. Errors may occur because of a lack of foundational knowledge in comprehensive risk assessment and on how to order the best test in a laboratory capable of detecting a pathogenic variant as well as how to interpret germline testing results. Increasing the number of genetics professionals, implementing new delivery models, and increasing educational efforts in nongenetics professionals could prevent and decrease errors.

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There are multiple laboratories that offer germline genetic testing, and it can be difficult to discern which one to use for testing. Some laboratories have more comprehensive analysis techniques and capability, which increases the accuracy of testing. The ordering provider has a responsibility to select the appropriate laboratory with technologic capability for the needed testing, inform the laboratory of prior testing results in the patient and family so known familial variants have targeted testing, and use appropriate terminology and nomenclature when communicating information to other healthcare professionals, patients, and families. This report presents a case illustrating the potential errors that can occur when a provider selects a laboratory that lacks the capacity to detect certain pathogenic variants, such as large deletions and duplications. False-negative germline testing results lead to missed opportunities in prevention and early detection for not only the patient but often multiple family members, which may lead to psychosocial distress and late-detected cancers. This case highlights the complexities of genetic care and why management by a genetics professional can facilitate more fiscally responsible care, appropriate genetic testing, and comprehensive care for all family members at risk.

For distress, standards of care are based on established evidence-based practice. Distress is a multifactorial and unpleasant emotional experience of a psychological (e.g., cognitive, behavioral, emotional), social, and/or spiritual nature that can interfere with the ability to effectively cope with a cancer diagnosis, physical symptoms and treatment, and long-term consequences of treatment. All patients are expected to experience some level of distress at some point in the cancer trajectory.

For peripheral neuropathy, standards of care are based on established evidence-based practice. Peripheral neuropathy is disease or dysfunction of one or more peripheral nerves (i.e., motor, sensory, or autonomic), resulting in numbness or weakness. Peripheral neuropathy occurs outside of the brain and spinal cord and is caused by cancer, treatment, or both. Chemotherapeutic agents that can cause peripheral neuropathy include epothilones, platinum analogs, taxanes, and vinca alkaloids, as well as immunomodulating drugs and proteasome inhibitors.

For hot flashes, standards of care are based on established evidence-based practice. Hot flashes are a sensation of heat that can be accompanied by facial flushing, perspiration, chills, heart palpitations, night sweats, and anxiety. Hot flashes occur in 51%-82% or women treated for breast cancer and 80% of men treated for prostate cancer with surgical or chemical castration.

For constipation, standards of care are based on established evidence-based practice. Constipation is the decreased passage of stool characterized by infrequent bowel movements, hard stool, a sensation of abdominal bloating or cramping, straining with bowel movements, and the feeling of incomplete evacuation. Constipation occurs in 43%-58% of people with a diagnosis of cancer.

For fatigue/lack of endurance, standards of care are based on established evidence-based practice. Fatigue is a distressing, persistent, and subjective sense of tiredness or exhaustion that is not proportional to the activity and interferes with usual function. Lack of endurance refers to limited physical capability to sustain an exercise or activity for an extended period of time. From 80% to 100% of patients with cancer report experiencing fatigue. It can be isolated or occur within a symptom cluster with pain, depression, dyspnea, anorexia, and sleep disturbance.

For lymphedema, standards of care are based on established evidence-based practice. Lymphedema is the accumulation of lymph fluid that obstructs the flow of the lymphatic system, causing persistent swelling of the affected body part. Lymphedema is most commonly seen after lymph node dissection or radiation therapy. It occurs in 10%-40% of patients with breast cancer and 80% of patients with lymph node dissection in the groin.

For genitourinary distress, standards of care are based on established evidence-based practice. Genitourinary distress is accidental urine leakage that can dampen underwear or saturate clothes. It is a sense of urgency, frequent urination, and/or pain or discomfort when urinating. Genitourinary distress is found in 35%-75% of patients with prostate cancer.