Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance

Tsai, Ginger J.; Rañola, John Michael O.; Smith, Christina; Garrett, Lauren; Bergquist, Timothy; Casadei, Silvia; Bowen, Deborah J.; Shirts, Brian H.

doi:10.1038/s41436-018-0335-7

Cited by 39 publications

(47 citation statements)

References 34 publications

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“…As a consequence, a low percentage of variants classified currently as VUS confer a real of risk in IAS and most are LB [21]. To discriminate a true risk-carrying variant from a non-deleterious variant is a challenge without accurate family segregation and functional studies [7]. Expected frequencies of each IAS variant and constant update of minor allele frequencies in large global population studies should be used to help identify the genes, regions of genes, and/or types of variants strongly associated with IAS which may help to determine the roles of variants in clinical settings, particularly if they are classified as VUS [22].…”

Section: Discussionmentioning

confidence: 99%

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Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

et al. 2020

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A B S T R A C TBackground: Accurate interpretation of rare genetic variants is a challenge for clinical translation. Updates in recommendations for rare variant classification require the reanalysis and reclassification. We aim to perform an exhaustive re-analysis of rare variants associated with inherited arrhythmogenic syndromes, which were classified ten years ago, to determine whether their classification aligns with current standards and research findings. Methods: In 2010, the rare variants identified through genetic analysis were classified following recommendations available at that time. Nowadays, the same variants have been reclassified following current American College of Medical Genetics and Genomics recommendations. Findings: Our cohort included 104 cases diagnosed with inherited arrhythmogenic syndromes and 17 postmortem cases in which inherited arrhythmogenic syndromes was cause of death. 71.87% of variants change their classification. While 65.62% of variants were classified as likely pathogenic in 2010, after reanalysis, only 17.96% remain as likely pathogenic. In 2010, 18.75% of variants were classified as uncertain role but nowadays 60.15% of variants are classified of unknown significance. Interpretation: Reclassification occurred in more than 70% of rare variants associated with inherited arrhythmogenic syndromes. Our results support the periodical reclassification and personalized clinical translation of rare variants to improve diagnosis and adjust treatment.

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Section: Discussionmentioning

confidence: 99%

“…Continuous reclassification is recommended to update their roles before clinical translation. Such re-evaluation may serve to improve psychological outcomes and risk stratification while promoting personalized management [6,7]. Only a few reports have addressed this idea in recent years [8À10].…”

Section: Introductionmentioning

confidence: 99%

Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

et al. 2020

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“…Research studies are available to help reclassify VUS, and these can be discussed with a genetic counselor. 17 In one study, 7.7% of VUS results were reclassified: 91% as benign/likely benign and 9% as pathogenic/likely pathogenic. 18 An outcome could also be that no mutations were identified (a benign result).…”

Section: Genetic Testingmentioning

confidence: 99%

Germline and Somatic Mutations in Prostate Cancer for the Clinician

Cheng

Sokolova

Schaeffer

et al. 2019

Journal of the National Comprehensive Cancer Network

100

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It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology, and acquired (somatic) mutations that occur in prostate cancer cells. In the advanced disease setting, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumor-directed somatic sequencing may guide treatment decision-making. This review provides clinicians with knowledge of basic genetic terminology, awareness of the importance of family history of cancer (not limited to prostate cancer), contrasts between the different but potentially related objectives of germline versus somatic testing of tumor tissue, and indications for genetic counseling. Specific clinical scenarios, objectives of testing, and nature of the assays are reviewed. Germline and somatic mutations of known and potential relevance to prostate cancer are discussed in the context of treatment options, and algorithms to assist clinicians in approaching this area are proposed.

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“…In previous work, we found that actively involving patients as collaborators in charge of family communication for their own VUS reclassification studies led to reclassification of approximately 60% of variants, with an average time to classification of <1 year (Makhnoon, Garrett, Burke, Bowen, & Shirts, ; Tsai et al, , ). Unique aspects of this process included conveying uncertainty related to the clinical significance of the variant, patients’ and relatives’ involvement in aspects that might be considered research activities, and communication with relatives extending beyond the first and second degree of relationship.…”

Section: Introductionmentioning

confidence: 99%

“…Family communication plays a vital role in facilitating patient‐driven family studies for VUS reclassification, in which families provide a unique source of phenotypic and genotypic information that increases the rate and impact of VUS reclassification (Tsai et al, ). Previous studies have addressed the extent, methods, and impact of family communication of genetic test results to relatives, along with the communication of associated genetic risks and medical management recommendations (Baars et al, ; Behavioral Working Group of the Colon Cancer Family Registry et al, ; Claes et al, ; Daly et al, ; Forrest et al, ; Hughes et al, ; Leenen et al, ; Patenaude et al, ; Stoffel et al, ; Vos et al, ).…”

Section: Introductionmentioning

confidence: 99%

Exploring relatives’ perceptions of participation, ethics, and communication in a patient‐driven study for hereditary cancer variant reclassification

Tsai

Chen

Garrett

et al. 2020

Journal of Genetic Counseling

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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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Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance

Cited by 39 publications

References 34 publications

Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

Germline and Somatic Mutations in Prostate Cancer for the Clinician

Exploring relatives’ perceptions of participation, ethics, and communication in a patient‐driven study for hereditary cancer variant reclassification

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