AP-534523-003 GENETIC SCREENING OF FAMILY MEMBERS IN AN ATRIAL FIBRILLATION PRECISION MEDICINE CLINIC

Heart Rhythm · 2026-04-01

P152: Systematic gaps in reporting variants of uncertain significance (VUS) and their reclassifications

Genetics in Medicine Open · 2026-01-01

Strategies to Assess Risk for Hereditary Cancer in Primary Care Clinics

JAMA Network Open · 2025-03-07 · 7 citations

Importance: Best practices for improving access to assessment of hereditary cancer risk in primary care are lacking. Objective: To compare 2 population-based engagement strategies for identifying primary care patients with a family or personal history of cancer and offering eligible individuals genetic testing for cancer susceptibility. Design, Setting, and Participants: The EDGE (Early Detection of Genetic Risk) clinical trial cluster-randomized 12 clinics from 2 health care systems in Montana, Wyoming, and Washington state to 1 of 2 engagement approaches for assessment of hereditary cancer risk in primary care. The study population included 95 623 English-speaking patients at least 25 years old with a primary care visit during the recruitment window between April 1, 2021, and March 31, 2022. Intervention: The intervention comprised 2 risk assessment engagement approaches: (1) point of care (POC), conducted by staff immediately preceding clinical appointments, and (2) direct patient engagement (DPE), where letter and email outreach facilitated at-home completion. Patients who completed risk assessment and met prespecified criteria were offered genetic testing via a home-delivered saliva testing kit at no cost. Main Outcomes and Measures: Primary outcomes were the proportion of patients with a visit who (1) completed the risk assessment and (2) completed genetic testing. Logistic regression models were used to compare the POC and DPE approaches, allowing for overdispersion and including clinic as a design factor. An intention-to-treat analysis was used to evaluate primary outcomes. Results: Over a 12-month window, 95 623 patients had a primary care visit across the 12 clinics. Those who completed the risk assessment (n = 13 705) were predominately female (64.7%) and aged between 65 and 84 years (39.6%). The POC approach resulted in a higher proportion of patients completing risk assessment than the DPE approach (19.1% vs 8.7%; adjusted odds ratio [AOR], 2.68; 95% CI, 1.72-4.17; P < .001) but a similar proportion completing testing (1.5% vs 1.6%; AOR, 0.96; 95% CI, 0.64-1.46; P = .86). Among those eligible for testing, POC test completion was approximately half of that for the DPE approach (24.7% vs 44.7%; AOR, 0.49; 95% CI, 0.37-0.64; P < .001). The proportion of tested patients identified with an actionable pathogenic variant was significantly lower for the POC approach than the DPE approach (3.8% vs 6.6%; AOR, 0.61; 95% CI, 0.44-0.85; P = .003). Conclusions and Relevance: In this cluster randomized clinical trial of risk assessment delivery, POC engagement resulted in a higher rate of assessment of hereditary cancer risk than the DPE approach but a similar rate of genetic testing completion. Using a combination of engagement strategies may be the optimal approach for greater reach and impact. Trial Registration: ClinicalTrials.gov Identifier: NCT04746794.

P656: Using functional data for VUS reclassification in cancer predisposition genes

Genetics in Medicine Open · 2025-01-01

the results from certain experiments as evidence within specific classification guidelines.As more functional data are generated by both clinical and research laboratories, it's critical to make the data findable and accessible to variant scientists and clinicians.Presenting functional data in ClinVar makes it easily accessible both to individual users on the ClinVar website and to software systems that process the entire ClinVar dataset or access it programmatically.

Cost-effectiveness of primary care-based risk assessment and hereditary cancer genetic testing

BMC Primary Care · 2025-12-22

Guidelines recommend identifying individuals with a family or personal history of cancer, offering genetic testing, with the goal of managing disease risk. Yet, risk assessment (“screening”) and genetic testing remain underutilized in the primary care setting and the value of an optimal strategy for engaging individuals is unknown. Our goal is to estimate the incremental cost, incremental effectiveness, and incremental cost-effectiveness ratio (ICER) between two population-based engagement strategies in proportions of individuals risk assessed and tested, by providing these services in a primary care setting. Data were obtained from the EDGE (Early Detection of GEnetic risk)-clinic-randomized controlled trial that evaluated two engagement strategies - an in-clinic point of care (POC) strategy and a direct participant engagement (DPE) strategy that involved (e)mailing invitations after a visit. At risk participants were offered complementary genetic testing and counseling. Using these data, we constructed a decision-analytic cohort model and compared the POC to DPE strategy. We modeled testing all clinic participants over a two-year timeframe and present results from both health-system and limited societal perspectives. Outcomes were the proportion of participants risk-assessed and tested, the costs for each strategy, and the ICERs. From the health-system perspective, costs for approaching 100,000 participants were $641,278 (POC) and $702,653 (DPE). The POC strategy led to 14,490 (46%) of participants completing risk assessment and the DPE strategy to 6,385 (7%) participants, thus POC dominated DPE for risk assessment completion (68% of simulations). The POC strategy led to fewer individuals completing testing than the DPE strategy [780 (73%) vs. 1,184 (77%)], revealing an ICER of $152 (health-system) and $136 (limited societal) perspectives in favor of DPE (52% and 58% of simulations). With substantial uncertainty, results suggest that the DPE strategy may provide good value for money spent on testing at a willingness-to-pay test-kit cost of $250. That the incremental cost-effectiveness of risk assessment versus testing contrasts, suggests that engagement approaches play an important role in shaping outcomes of population-based risk assessments. A hybrid approach (DPE, followed by POC for those who do not respond) may be optimally cost-effective. NCT04746794; Date: February 4, 2021.

P215: Assessment of factors driving disparities in clinical uncertainty for patients seen in adult medical genetics clinics

Genetics in Medicine Open · 2025-01-01

ineligible.From multiracial patients (n=583), 22% were ineligible.From other patients (n=2,927), 22% were ineligible.From White patients (n=4,369), 19% were ineligible.From Ashkenazi Jewish patients (n=258), 17% were ineligible.Compared to White individuals, Black (p<0.001) and Hispanic individuals (p<0.001) were significantly more likely to have a P/LP variant ineligible for HEMT.Of the 10 most frequent modulator ineligible variants, 60% (6/10) could be targeted by HEMT, as they were predicted to result in some CFTR protein production.Conclusion: Differences in modulator eligibility across racial and ethnic groups were seen when CFTR variants were examined in a large cohort of patients receiving CS, reflecting broader disparities in CF treatment eligibility.Our results provide valuable information for educating patients at the time of carrier screening regarding treatment availability for children who may be affected by CF.To promote equitable access to advancements in treatment, further research is needed to determine if some currently ineligible variants are responsive to existing modulator treatment.

Imprecision medicine: Systematic gaps in reporting variants of uncertain significance (VUS) and their reclassifications

Genetics in Medicine · 2025-06-18 · 1 citations

Long-read DNA and RNA sequencing for inherited polyposis and colorectal cancer: cryptic intronic variants and multiple mutational mechanisms

Journal of Medical Genetics · 2025-06-26 · 3 citations

Background Molecular genetic diagnoses are critical to prevention and treatment of inherited polyposis and colorectal cancer. 19 genes responsible for these conditions are known, but many severely affected patients and families remain unsolved. Cryptic intronic variants that alter splicing of these genes and incomplete characterisation of recessive predisposition contribute to these diagnostic gaps. Methods Adaptive sampling long-read DNA sequencing targeted to 19 colon cancer genes, paired with direct long-read RNA whole-transcriptome sequencing, was undertaken for four patients referred for deficiency of mismatch repair proteins and/or familial polyposis, for whom multigene panel testing yielded negative or uncertain germline results. Results Genetic diagnoses were obtained for all four patients. Each patient carried a cryptic intronic germline variant in a different colon cancer gene. The variants abrogated splicing by various mechanisms, all leading to loss of gene function. Patient 1 was heterozygous for intronic insertion into MSH2 of an Alu element, leading to extension of transcription into the affected intron and a stop. Patient 2 was heterozygous for deep intronic insertion into APC of a Long Interspersed Nuclear Element (LINE), creating a pseudoexon and a stop. Patient 3 was compound heterozygous at MLH3 , including a cryptic intronic substitution leading to exon skipping and a stop. Patient 4 was compound heterozygous at MUTYH , including a deep intronic deletion yielding an extremely short intron and transcriptional loss of an exon encoding a critical protein domain. Conclusion Paired long-read DNA and RNA sequencing can enhance diagnostic yield through detection of cryptic intronic variants that impact cancer predisposition.

Insights on improving accessibility and usability of functional data to unlock its potential for variant interpretation

medRxiv · 2025-01-27 · 2 citations

Introduction: Variant-level functional data is a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUS). However, the usage of functional data by genetics professionals is currently unknown. Methods: An online survey was developed and distributed in spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses. Results: 190 eligible individuals responded, with 93% reporting interpreting 26 or more variants per year. The median respondent reported 11-20 years of experience. The most common professional roles were laboratory medical geneticists (23%) and variant review scientists (23%). 77% reported using functional data for variant interpretation in a clinical setting and overall respondents felt confident in assessing functional data. However, 67% indicated that functional data for variants of interest was rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to its use. 94% of respondents noted that better access to primary functional data and standardized interpretation of functional data would improve usage. Respondents also indicated that handling conflicting functional data is a common challenge in variant interpretation that is not performed in a systematic manner across institutions. Discussion: The results from this survey showed a demand for a comprehensive database with reliable quality metrics to support use of functional evidence in clinical variant interpretation. The results also highlight a need for guidelines regarding how putatively conflicting functional data should be used for variant classification.

Insights on improving accessibility and usability of functional data to unlock their potential for variant interpretation

The American Journal of Human Genetics · 2025-06-01 · 11 citations