American College of Medical Genetics and Genomics 2025 Posters

Our researchers unveiled new clinical research from the Helix Research Network^TM (HRN) and its partners at the 2025 ACMG Annual Clinical Genetics Meeting showcasing how genomic screening can not only accurately identify high-risk individuals but also improve adherence to recommended care.

The novel research goes further to demonstrate how real-world evidence can enable precision medicine through personalized monitoring plans based on individual risk and improve and automate the interpretation of genetic variations for increased accuracy.

Read below for a summary of the posters we presented and to download them:

Tailoring surveillance strategies for PMS2 heterozygotes

• Objective: Determine the risk of cancer associated with pathogenic
  variants in MLH1, MSH2, MSH6 or PMS2 in the general population, and test the assumptions made by current clinical guidelines.
• Results: We found attenuated clinical impact for pathogenic variants in PMS2, even when restricting to exons 1-10 to avoid any false positives due to
  pseudogene, with similar results observed in UK Biobank and All of Us.
• The question remains on what is best surveillance strategy for PMS2 heterozygotes.
• One option to test: start colonoscopies at same age as average population (age 45y) and repeat every 1-3 years after that.
• This approach could reduce the number of colonoscopies by 7+ per PMS2 heterozygote.

Clinical impact of having a pathogenic variant in Lynch genes

The benefits of identifying individuals at lower risk of disease in the population

• New challenge was to identify individuals at low risk of disease given the benefits include:
  • Reallocation of resources towards those at high risk
  • Reduce avoidable costs for individual patients
  • Enhance compliance, especially for those at average risk
• Objective: Use breast cancer as a proof of concept to create a framework to identify those at low risk of disease, assess potential benefits and provide data to justify including a "low risk category" as a potential return of result when screening the population.
• Results: We found delaying the age to start mammogram screening for women in low-risk group could optimize health care resource allocation.
• It could save ~300,000 mammograms each year in the US.
  The framework established for breast cancer can be leveraged for
  other conditions, including colorectal cancer or coronary artery disease.

Clinical validity

Confidently resolve truncating variants in APOB as benign for Familial Hypercholesterolemia

• Objective: Investigate the clinical impact of APOB truncating variants in large unselected populations to streamline the interpretation of these variants in the context of Familial Hypercholesterolemia (FH).
• Results: We found APOB p.Arg3527Gln had a significant clinical impact on FH-related disease in the general population despite being relatively common.
• APOB pLOF variants are protective against FH-related disease and should be returned as Benign in the context of screening for FH.
• A similar approach can be used for all genes where haploinsufficiency is NOT the mechanism of disease.
• Clear evidence that pLOF variants are not pathogenic in these scenarios will reduce the burden of variant interpretation without decreasing the accuracy
  of the screening.

Clinical impact of having a truncating variant in APOB

Adverse events increased by 38% in individuals who should not take clopidogrel

• Objective: Use retrospective CYP2C19 results to stratify individuals by whether their clopidogrel treatment was appropriate in retrospect.
• Results: We found individuals who should not take clopidogrel are common in every population.
• Individuals who should not take clopidogrel are ~2x more likely to have excess adverse events.
• The cost of excess thromboses and MIs experienced by individuals who should not take clopidogrel is ~$700k/1000 patients.

Adverse events enriched 2x in poor metabolizers and intermediate metabolizers

Improving variant interpretation with a
common PS4 and benign evidence approach

• Objective: Develop a universal resource for PS4 and benign variants that could be created from biobanks.
• Results: We found 6.9% of variants powered for analysis, which covered 77% of carriers.
• For adequately powered variants, statistical evidence lines up well with established ACMG calls.
• Overall, 8.6% of VUS calls have adequate statistical evidence which corresponds to 57% of VUS carriers.
  • This varied by condition: HBOC 12%; LS 39%; FH 75%

Genetically predicted Lp(a) levels accurately identify individuals at risk of cardiovascular complications

• Objective: Develop an exome-based KIV-2 exon copy number estimate using the all-comers Helix Research Network data.
• Results: We found our exome-based predictor of Lp(a) works across populations.
• This predictor is associated with 1.5-2 fold increased disease risk.
• Individuals with disease unexplained by traditional risk factors are 2x more likely to have high genetic risk of a high Lp(a).
• Genetically estimated Lp(a) can identify high risk individuals without an Lp(a) test.

Lp(a) contributes to unexpected ASCVD

Automated variant interpretation shows accuracy equivalent to ACMG/AMP-based interpretation for CDC Tier 1 conditions

• Objective: Develop a version of the ACMG/AMP interpretation standard, which was originally developed for diagnostic testing, specifically for screening that can be applied automatically to all variants for prospective risk assessment.
• Results: We found interpretations from our screening approach show high sensitivity and specificity compared to standard diagnostic interpretations.
• In retrospective analyses of clinicogenomic data, hazard ratios (HRs) for individuals harboring
  pathogenic variants called using our screening interpretation approach are in line with risk estimates reported from disease-specific cohorts.
• We see differences in disease rates and onset across the high (MLH1/MSH2)
  and low (PMS2/MSH6) penetrance Lynch Syndrome genes.
• Individuals harboring VUS, even split into higher and lower scoring groups,
  show little evidence of increased disease risk, which supports returning only
  pathogenic variant interpretations in screening scenarios.

Improved breast cancer screening adherence among participants receiving a negative result from a multi-health system Population Genomics Screening program

• Objective: Evaluate adherence to standard breast cancer screening among individuals who received negative BRCA1 and BRCA2 results through a health system-initiated population genomic screening network before and after participation in the screening program.
• Results: We found population genomic screening program studies typically focus on identifying patients with a positive finding and their downstream management.
• Our study evaluates the patients who screen negative in these programs and their follow-up care, specifically women and their breast cancer screening adherence.
• We demonstrated that women receiving a negative result from their CDCT1 screening significantly improved their general breast cancer screening adherence.
• Importantly, this behavior appears to be sustained over time. This finding
  reinforces prior studies in which participants with negative findings did not intend to forgo routine screening.
• Our analysis suggests minimal impact of false reassurance, and, more importantly, that population genomic screening programs yield benefit to all comers not only participants with a positive screening.

Proportion of participants with breast cancer screening at least every two years

Impact of Population Genomic Screening on Patient Behavior and Care: Changes in Preventive Screening Behaviors Among HBOC Positive Individuals

• Objective: Investigate the impact of population genomic screening on patient behavior and management, focusing on uptake of updated breast cancer preventive screening recommendations among HBOC positive individuals.
• Results: Additionally, we aimed to explore factors contributing to patients' uptake of updated guidelines.
• We found this study provides evidence of the impact of population genomic screening on patient behavior and care among HBOC-positive individuals.
• The findings suggest that population genomic screening programs effectively identify high-risk individuals and lead to increased adherence to care recommendations and breast cancer screening rates.
• However, further efforts are needed to engage individuals who were not adherent with screening prior to enrollment and sustain long-term engagement in screening.
• Implementing population genomic screening has the potential to enhance early detection and management of HBOC, ultimately improving patient outcomes.
• Continued research is necessary to evaluate the long-term implications, cost-effectiveness, and strategies to engage and retain hard-to-reach populations in large-scale screening programs.

Logistic regression results