Multi-gene cancer panels often identify variants of uncertain clinical significance (VUS) that pose a challenge to health care providers in managing a patient’s cancer risk. Family segregation analysis can yield powerful data to re-classify a VUS (as either benign or pathogenic). However, financial and personnel resources to coordinate these studies are limited. In an informal assessment we found that family studies for variant classification are done by most clinical genetics laboratories that offer hereditary cancer panel testing. The process for family studies differs substantially across laboratories. One near universal limitation is that families usually have too few individuals for an informative co-segregation analysis. A unique and potential resource-saving approach is to engage patients and their families in expanding their own pedigrees for segregation analysis of their VUS. We describe a novel public educational tool (FindMyVariant.org) designed to inform patients and genetic counselors about strategies to improve the probability of variant classification using familial segregation. While the web tool is designed to be useful for any gene, the project was primarily focused on VUS’s returned in cancer risk genes. FindMyVariant.org is a resource for genetic providers to offer motivated families who are willing to gather information about their family relationships and history. Working alongside clinical or research genetic laboratories, the information they collect may help reclassify their VUS using segregation analysis.
Patients' understanding of a genetic variant of unknown clinical significance (VUS) is likely to influence beliefs about risk implications, consequent medical decisions, and other actions such as involvement in research. We interviewed 26 self-selected participants with a clinically identified VUS before they enrolled into a VUS reclassification study. Semi-structured interviews addressed topics including motivation to get genetic test, experience with the VUS result, affective responses to receiving VUS, and perceived effect of VUS and reclassification on medical care. We found that family and personal history of disease were the most prevalent motivators for getting a genetic test. Participants demonstrated mixed understanding of VUS. Most expressed negative effect on learning of their VUS result and uncertainty about its impact on clinical management. Most expected reclassification efforts to benefit their family members but not themselves. Some expressed distrust of their providers following a VUS result. Participation in the VUS reclassification study appeared to be motivated by four factors for patients with VUS-negative effect about VUS, uncertainty about its impact on clinical management, concern for family members' well-being, and to advance science. Perhaps the direct acknowledgement and appraisal of uncertainty as a means of coping was missing in some pre-test counseling experienced by our participants and thus they were not psychologically prepared for atypical VUS results. The finding of VUS-induced provider distrust suggests a need for careful consideration of appropriate pre- and post-test counseling about VUS.
Effective communication of genetic information within families depends on several factors. Few studies explore intra-familial communication of variant of uncertain significance (VUS) results or active collaboration between family members to classify VUS. Our qualitative study aimed to describe the experiences of individuals asked by family members to participate in the FindMyVariant study, a patient-driven family study which aimed to reclassify a clinically identified familial VUS in a hereditary cancer gene. We collected feedback from 56 individuals from 21 different families through phone interviews and written correspondence, transcribed the interviews, and performed thematic analysis on all text. We describe themes from three main topics: participation, ethical considerations, and study impacts. Participation in the FindMyVariant study, defined as returning a sample for targeted genotyping, was motivated by convenience and a desire to help the family, oneself, and science. Relatives were generally responsive to invitations to participate in FindMyVariant from another family member. Those who declined to participate did so due to concerns about research program confidentiality rather than family dynamics. No major ethical issues arose in response to the patient-driven study structure, and no major changes in stress and anxiety, medical care, or behavior occurred. Participation in patient-driven familial VUS classification studies has a neutral or positive impact on family health communication. While it is important to design studies to minimize familial coercion, intra-familial confidentiality breaches, and misinterpretation of genetic results, these were not major concerns among relatives in this study. Clinicians and laboratories may consider encouraging familial communication about genetic variants using family members as liaisons.
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