Applying health equity implementation science frameworks to population genetic screening.

Introduction: Implementation science frameworks with a focus on health equity have emerged to help guide the introduction of new interventions into healthcare and community settings while limiting health disparities. The purpose of this research was to explore the applicability of such frameworks to guide the equitable implementation of population genetic screening programs.

Methods: We searched PubMed and reference lists for relevant frameworks and examples of their use in health settings.

Primary care provider practices, attitudes, and confidence with hereditary cancer risk assessment and testing: A mixed methods study.

Purpose: This study sought to better understand primary care providers' (PCPs) readiness to conduct population-based risk assessment and offer genetic testing for hereditary cancer.

Methods: Sixty PCPs completed a survey assessing their current practices, attitudes, and confidence with cancer risk assessment and testing. Sixteen participated in follow-up interviews.

A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.

Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline.

Assigning credit where it is due: an information content score to capture the clinical value of multiplexed assays of variant effect.

Background: A variant can be pathogenic or benign with relation to a human disease. Current classification categories from benign to pathogenic reflect a probabilistic summary of the current understanding. A primary metric of clinical utility for multiplexed assays of variant effect (MAVE) is the number of variants that can be reclassified from uncertain significance (VUS).

A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.

Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, , are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked to a mutator phenotype affecting normal somatic cells as well as the female germline.

ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification.

The 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification publication established a standard employed internationally to guide laboratories in variant assessment. Those recommendations included both pathogenic (PP1) and benign (BS4) criteria for evaluating the inheritance patterns of variants, but details of how to apply those criteria at appropriate evidence levels were sparse. Several publications have since attempted to provide additional guidance, but anecdotally, this issue is still challenging.

Assigning credit where it's due: An information content score to capture the clinical value of Multiplexed Assays of Variant Effect.

Background: A variant can be pathogenic or benign with relation to a human disease. Current classification categories from benign to pathogenic reflect a probabilistic summary of current understanding. A primary metric of clinical utility for multiplexed assays of variant effect (MAVE) is the number of variants that can be reclassified from uncertain significance (VUS).

Exploring Stakeholders' Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings From a Clinical Practice Survey.

Purpose: New guidelines recommend considering germline genetic testing for all patients with colorectal cancer (CRC). However, there is a lack of data on stakeholders' perspectives on the advantages and barriers of implementing universal germline testing (UGT). This study assessed the perspectives of members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) regarding the implementation of UGT for patients with CRC, including readiness, logistics, and barriers.

Factors Influencing Genetic Screening Enrollment among a Diverse, Community-Ascertained Cohort.

Introduction: Genetic screening for preventable adult-onset hereditary conditions has been proposed as a mechanism to reduce health disparities. Analysis of how race and ethnicity influence decision-making to receive screening can inform recruitment efforts and more equitable population screening design. A study at the University of Washington Medicine that invited unselected patients to participate in genetic screening for pathogenic variation in medically important genes provided an opportunity to evaluate these factors.

Current chemoprevention approaches in Lynch syndrome and Familial adenomatous polyposis: a global clinical practice survey.

Background: International chemoprevention preferences and approaches in Lynch syndrome (LS) and associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored.

Aim: To describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey.

Results: Ninety-six participants across four hereditary gastrointestinal cancer societies responded to the survey.

Extended Family Outreach in Hereditary Cancer Using Web-Based Genealogy, Direct-to-Consumer Ancestry Genetics, and Social Media: Mixed Methods Process Evaluation of the ConnectMyVariant Intervention.

Background: Cascade screening, defined as helping at-risk relatives get targeted genetic testing of familial variants for dominant hereditary cancer syndromes, is a proven component of cancer prevention; however, its uptake is low. We developed and conducted a pilot study of the ConnectMyVariant intervention, in which participants received support to contact at-risk relatives that extended beyond first-degree relatives and encourage relatives to obtain genetic testing and connect with others having the same variant through email and social media. The support that participants received included listening to participants' needs, assisting with documentary genealogy to find common ancestors, facilitating direct-to-consumer DNA testing and interpretation, and assisting with database searches.

Diagnostic yield of genetic screening in a diverse, community-ascertained cohort.

Background: Population screening for genetic risk of adult-onset preventable conditions has been proposed as an attractive public health intervention. Screening unselected individuals can identify many individuals who will not be identified through current genetic testing guidelines.

Methods: We sought to evaluate enrollment in and diagnostic yield of population genetic screening in a resource-limited setting among a diverse population.

Using species richness calculations to model the global profile of unsampled pathogenic variants: Examples from BRCA1 and BRCA2.

There have been many surveys of genetic variation in BRCA1 and BRCA2 to identify variant prevalence and catalogue population specific variants, yet none have evaluated the magnitude of unobserved variation. We applied species richness estimation methods from ecology to estimate "variant richness" and determine how many germline pathogenic BRCA1/2 variants have yet to be identified and the frequency of these missing variants in different populations. We also estimated the prevalence of germline pathogenic BRCA1/2 variants and identified those expected to be most common.

Optimising clinical care through -specific germline variant curation: improvement of clinical assertions and updated curation guidelines.

Background: Germline pathogenic variants in are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) Variant Curation Expert Panel (VCEP) developed specifications for variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.

A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian and colorectal cancer susceptibility genes.

Background: Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) that have an unknown impact on health but can be clarified through reclassification. There is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, and racial/ethnic differences.

Methods: This was a retrospective analysis of persons with and without a personal history of cancer carrying VUS (with or without an accompanying pathogenic or likely pathogenic [P/LP] variant) in breast, ovarian, and colorectal cancer predisposition genes seen at four cancer care settings (in Texas, Florida, Ohio, and New Jersey) between 2013 and 2019.

Implementation of pharmacogenomic clinical decision support for health systems: a cost-utility analysis.

We constructed a cost-effectiveness model to assess the clinical and economic value of a CDS alert program that provides pharmacogenomic (PGx) testing results, compared to no alert program in acute coronary syndrome (ACS) and atrial fibrillation (AF), from a health system perspective. We defaulted that 20% of 500,000 health-system members between the ages of 55 and 65 received PGx testing for CYP2C19 (ACS-clopidogrel) and CYP2C9, CYP4F2 and VKORC1 (AF-warfarin) annually. Clinical events, costs, and quality-adjusted life years (QALYs) were calculated over 20 years with an annual discount rate of 3%.

Laboratory-related outcomes from integrating an accessible delivery model for hereditary cancer risk assessment and genetic testing in populations with barriers to access.

Purpose: This study aimed to evaluate the laboratory-related outcomes of participants who were offered genomic testing based on cancer family history risk assessment tools.

Methods: Patients from clinics that serve populations with access barriers, who are screened at risk for a hereditary cancer syndrome based on adapted family history collection tools (the Breast Cancer Genetics Referral Screening Tool and PREMM), were offered exome-based panel testing for cancer risk and medically actionable secondary findings. We used descriptive statistics, electronic health record review, and inferential statistics to explore participant characteristics and results, consultations and actions related to pathogenic/likely pathogenic variants identified, and variables predicting category of findings, respectively.

An algorithm for optimal testing in co-segregation analysis.

Clinical genetic sequencing tests often identify variants of uncertain significance. One source of data that can help classify the pathogenicity of variants is familial cosegregation analysis. Identifying and genotyping relatives for cosegregation analysis can be time consuming and costly.

Harmonizing variant classification for return of results in the All of Us Research Program.

The All of Us Research Program (AoURP) is a historic effort to accelerate research and improve healthcare by generating and collating data from one million people in the United States. Participants will have the option to receive results from their genome analysis, including actionable findings in 59 gene-disorder pairs for which disorder-associated variants are recommended for return by the American College of Medical Genetics and Genomics. To ensure consistent reporting across the AoURP, in a prelaunch study the four participating clinical laboratories shared all variant classifications in the 59 genes of interest from their internal databases.

Inherited TP53 Variants and Risk of Prostate Cancer.

Background: Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53.

Objective: To determine whether gTP53 predisposes to prostate cancer.

Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN.

Clinical interpretation of missense variants is challenging because the majority identified by genetic testing are rare and their functional effects are unknown. Consequently, most variants are of uncertain significance and cannot be used for clinical diagnosis or management. Although not much can be done to ameliorate variant rarity, multiplexed assays of variant effect (MAVEs), where thousands of single-nucleotide variant effects are simultaneously measured experimentally, provide functional evidence that can help resolve variants of unknown significance (VUSs).

Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative.

Unlabelled: Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement.

Methods: Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016.