The Genetics Update: Evaluating a Patient Platform to Deliver Updated Genomic Results

Genomic sequencing (GS) is a driver of precision medicine: Clinicians are using GS for precision medicine, to diagnose patients and tailor recommendations about their medical care. Germline GS offers increased sensitivity over classic genetic tests, decreasing time-consuming and costly diagnostic cascades.

Genomic test results can change over time: Variants are classified as pathogenic (P), likely pathogenic (LP), VUS, likely benign (LB), or benign (B) per guidelines. However, the evidence on variants in disease changes constantly. Over time, laboratories reanalyze variants and genes, taking into new evidence and updated standards for interpretation.4 Reanalysis may result in a variant being reclassified (e.g. from VUS to P, or LB to B). On average, reclassification takes between 6 months and 2 years after a variant is first identified.5 Ideally, people with reclassified variants should be recontacted as soon as possible within this time frame. Among cancer genes, as many as 38% of reanalyzed variants are reclassified, and this rate can be as high as 43% among VUS. Up to 25% of VUS are reclassified as LP/P, and the remaining 75% downgraded to LB/B. In the context of cancer, such reclassifications have the potential to bring relief to a patient with a VUS, or to indicate their need for more urgent care and/or a refined treatment pathway.

Reclassification can affect patients' care: Identification of novel genomic changes, discovery of novel gene-disease associations, and/or variant reclassifications, (e.g. changes to or from LP/P) can trigger significant changes to patients' management. These changes can include altered frequency and/or types of surveillance, modified surgical recommendations, cascade testing for relatives or removal from a clinical trial. Even reclassifications that typically will not modify management, such as from VUS to LB/B, have the potential to relieve patient and provider uncertainty, and to reduce the risk of inappropriate actions being taken on the basis of the VUS. All of these changes in care depend on timely awareness of the patient (and/or) provider of the reclassification and its implications, particularly when updated genomic results are expected to impact clinical management; all of which are reinforced by international guidelines.

Cancer is the most common condition for which patients will need to be recontacted: Oncologists use tumour and germline GS to identify therapies, and improve diagnosis and management. And as its cost decreases, GS is expected to replace single gene or multigene panel testing as standard of care.

Patients want to be recontacted but waiting for updates causes patient distress: Internationally, patients and providers agree that recontact is desirable, though practically challenging. Patients value reanalysis of their genomic results over time and want to be recontacted with updates to their genomic results, even those with no impact on their medical care. Some cancer patients have been found to experience intrusive thoughts and worry about their genetic cancer risk while waiting for genetic results. Patients who receive VUS report elevated genetic-test specific distress; waiting for updates about VUS may result in further distress. Patients who are recontacted have been found to experience relief from both upgraded and downgraded results, and have been found not to experience distress or reduced trust in medical genetics. Innovative approaches are needed to feasibly recontact patients to deliver updates.