Patient experiences with clinical confirmatory genetic testing after using direct-to-consumer raw DNA and third-party genetic interpretation services.

The availability of raw DNA and genetic interpretation tools allow individuals to access genetic health risk information, where analytical false-positives exist. Little is known about the experience of individuals who receive pathogenic or likely pathogenic variant(s) through raw DNA interpretation and follow-up with clinical confirmatory genetic testing. This qualitative study set out to describe the experiences of individuals who pursued clinical confirmatory genetic testing, including their perception of the process. Participants were recruited from social media and eligible if they discovered a potential pathogenic or likely pathogenic variant in a raw DNA interpretation report, completed clinical confirmatory genetic testing in the U.S., and provided documentation of those results. Individuals participated in semi-structured interviews, which were transcribed and inductively coded to identify themes. Of the 12 participants, 3 received clinical genetic testing results that confirmed pathogenic or likely pathogenic variants noted in raw DNA interpretation reports (confirmation positive), and 9 were not confirmed. Nearly all (n = 11) participants described emotional distress and information-seeking behavior as a coping mechanism after discovering a pathogenic or likely pathogenic variant in raw DNA interpretation. When pursuing confirmatory genetic testing, many (n = 9) faced challenges with finding knowledgeable healthcare providers and obtaining insurance coverage. Despite reporting concerns over raw DNA interpretation and a desire for more safeguards, almost all (n = 10) participants stated interest in using the service again. Overall, participants' experiences reveal they find personal utility in raw DNA interpretation results and provide insight into opportunities for patient and provider education.

The availability of raw DNA data and online genetic interpretation tools allow individuals to access genetic health risk information, where false-positive results exist. Little is known about the experience of individuals who discover disease-causing variant(s) through raw DNA interpretation and follow-up with medical-grade confirmatory genetic testing. This qualitative study describes the experiences of individuals who pursued medical-grade confirmatory genetic testing in the U.S. after they discovered a potential disease-causing variant in a raw DNA interpretation report. Individuals participated in semi-structured interviews, which were transcribed and inductively coded to identify themes. Of the 12 participants, 3 received medical-grade genetic testing results that confirmed disease-causing variants noted in raw DNA interpretation reports, and 9 were not confirmed. Nearly all participants described emotional distress and information-seeking behavior after discovering a disease-causing variant in raw DNA interpretation. When pursuing confirmatory genetic testing, many faced challenges with finding knowledgeable healthcare providers and obtaining insurance coverage. Despite reporting concerns over raw DNA interpretation and a desire for more safeguards, almost all participants stated interest in using the service again. Overall, participants' experiences reveal they find personal utility in raw DNA interpretation results and provide insight into opportunities for patient and provider education.

Risk assessment and genetic counseling for Lynch syndrome - Practice resource of the National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer.

Identifying individuals who have Lynch syndrome involves a complex diagnostic workup that includes taking a detailed family history and a combination of various tests such as immunohistochemistry and/or molecular which may be germline and/or somatic. The National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer have come together to publish this practice resource for the evaluation of Lynch syndrome. The purpose of this practice resource was to provide guidance and a testing algorithm for Lynch syndrome as well as recommendations on when to offer testing. This practice resource does not replace a consultation with a genetics professional. This practice resource includes explanations in support of this and a summary of background data. While this practice resource is not intended to serve as a review of Lynch syndrome, it includes a discussion of background information and cites a number of key publications which should be reviewed for a more in-depth understanding. This practice resource is intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses, and other healthcare providers who evaluate patients for Lynch syndrome.

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study.

BACKGROUND: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS: Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. CONCLUSIONS: This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

Utilization of breast cancer risk prediction models by cancer genetic counselors in clinical practice predominantly in the United States.

Risk assessment in cancer genetic counseling is essential in identifying individuals at high risk for developing breast cancer to recommend appropriate screening and management options. Historically, many breast cancer risk prediction models were developed to calculate an individual's risk to develop breast cancer or to carry a pathogenic variant in the BRCA1 or BRCA2 genes. However, how or when genetic counselors use these models in clinical settings is currently unknown. We explored genetic counselors' breast cancer risk model usage patterns including frequency of use, reasons for using or not using models, and change in usage since the adoption of multi-gene panel testing. An online survey was developed and sent to members of the National Society of Genetic Counselors; board-certified genetic counselors whose practice included cancer genetic counseling were eligible to participate in the study. The response rate was estimated at 23% (243/1,058), and respondents were predominantly working in the United States. The results showed that 93% of all respondents use at least one breast cancer risk prediction model in their clinical practice. Among the six risk models selected for the study, the Tyrer-Cuzick (IBIS) model was used most frequently (95%), and the BOADICEA model was used least (40%). Determining increased or decreased surveillance and breast MRI eligibility were the two most common reasons for most model usage, while time consumption and difficulty in navigation were the two most common reasons for not using models. This study provides insight into perceived benefits and limitations of risk models in clinical use in the United States, which may be useful information for software developers, genetic counseling program curriculum developers, and currently practicing cancer genetic counselors.

At-home genetic testing in pediatrics.

PURPOSE OF REVIEW: This review discusses the state of at-home genetic testing, including both direct-to-consumer and consumer-directed genetic testing, for children. RECENT FINDINGS: At-home genetic testing continues to increase in popularity and laboratories are starting to offer tests geared towards newborns and children. Available at-home genetic tests for children address ancestral descent, supplement newborn screening, or provide risks for childhood and adult-onset disorders as well as pharmacogenomic data. However, there are aspects of at-home testing that are unique to children that both providers and parents need to be aware of before considering this type of testing; these include issues related to motivations for testing; privacy concerns; result interpretation; ethical, legal and social implications; and impact on family relationships, among others. SUMMARY: This review addresses the challenges associated with at-home genetic testing in children and provides guidance for pediatricians and other health care providers who field inquiries about this type of testing or who are presented with at-home genetic test results for interpretation.

Coordinating an Oncology Precision Medicine Clinic Within an Integrated Health System: Lessons Learned in Year One.

Precision medicine is a term describing strategies to promote health and prevent and treat disease based on an individual's genetic, molecular, and lifestyle characteristics. Oncology precision medicine (OPM) is a cancer treatment approach targeting cancer-specific genetic and molecular alterations. Implementation of an OPM clinical program optimally involves the support and collaboration of multiple departments, including administration, medical oncology, pathology, interventional radiology, genetics, research, and informatics. In this review, we briefly introduce the published evidence regarding OPM's potential effect on patient outcomes and discuss what we have learned over the first year of operating an OPM program within an integrated health care system (Aurora Health Care, Milwaukee, WI) comprised of multiple hospitals and clinics. We also report our experience implementing a specific OPM software platform used to embed molecular panel data into patients' electronic medical records.

The dawn of consumer-directed testing.

As the public's interest in genetics and genomics has increased, there has been corresponding and unprecedented growth in direct-to-consumer genetic testing (DTC-GT). Although regulatory concerns have limited true DTC-GT available without a physician order, the paradigm has shifted to a model of consumer-directed genetic testing (CD-GT) in which patients are researching testing options and requesting specific genetic testing from their health-care providers. However, many nongenetics health-care providers do not have the background, education, interest, or time to order and/or interpret typical clinical genetic testing, let alone DTC-GT. The lines between CD-GT, DTC-GT, and traditional clinical genetic testing are also blurring with the same types of tests available in different settings (e.g., carrier screening) and tests merging medical and nonmedical results, increasing the complexity for consumer decision-making and clinician management. The genetics community has the training to work with CD-GT, but there has been a hesitancy to commit to working with these results and questions about what to do when consumers have more complicated asks, like interpretation of raw data. Additionally, at the rate with which CD-GT is growing, there are questions about having sufficient genetics professionals to meet the potential genetic counseling demand. While there are many complex questions and challenges, this market represents a chance for the genetics community to address and unmet need. We will review the history of the CD-GT/DTC-GT market and outline the issues and opportunities our profession is facing.

FDA Approval of PARP Inhibitors and the Impact on Genetic Counseling and Genetic Testing Practices.

In December 2014, the FDA approved olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) for ovarian cancer patients who have failed three or more lines of chemotherapy and have a germline BRCA1/2 mutation identified through a companion diagnostic test (BRACAnalysis CDx™ (CDx™)) offered exclusively by Myriad Genetic Laboratories. This study explored the impact of PARPi/CDx™ on genetic counselors' (GCs) counseling and testing practices. One hundred twenty three GCs responded to an online survey regarding pre- and post-FDA approval referral patterns, testing strategies/influences, and anecdotal experiences with insurance coverage of PARPi for BRCA1/2 positive patients through a non-CDx™ platform. Following PARPi approval, 40% of respondents reported an increase in overall referrals of ovarian cancer patients and 20% had an increase in post-test counseling only referrals. The majority (61.9%) of respondents reported no change in genetic testing strategy, and there was no change in factors influencing choice of testing laboratory. Nearly all (98.1%) respondents who had experience with insurance covering PARPi indicated approval with mutations identified via non-CDx™ testing. Respondents indicated an increase in referral volume following FDA approval of PARPi/CDx™, but did not report changes in testing practices. Respondents were not aware of PARPi insurance coverage denial in the absence of CDx™.

Implementing a Virtual Health Telemedicine Program in a Community Setting.

Aurora Health Care in eastern Wisconsin has a clinical genetics program driven by genetic counselors in the cancer/adult and prenatal genetics settings. In 2015, the workforce shortage of genetic counselors left us with 4 open positions for genetic counselors that we were unable to fill. We explored many models of alternative service delivery, and determined virtual health (VH) via telemedicine to be the best option for our system. Historically, telemedicine technologies have been used to provide access to healthcare services to patients in remote areas. We, however, were struggling to find genetics counselors to staff both our remote clinics and urban clinics. To solve this problem, we recruited genetic counselors from across the country to work remotely from their current home or home office utilizing VH to staff our clinics. We then created clinical workflows and an implementation process of virtual health for 9 prenatal and cancer clinics across the eastern Wisconsin footprint of our healthcare system over the course of 12 months. Here we provide our experience and process in establishing a VH program in order to help other institutions that have been affected by the workforce shortage of clinical genetics professionals.

Evaluation of laboratory perspectives on hereditary cancer panels.

Genetic counseling and testing for hereditary cancer susceptibility is a rapidly evolving field and partly a result of next-generation sequencing (NGS) allowing analysis of multiple cancer susceptibility genes simultaneously. This qualitative study explored laboratory perspectives on hereditary cancer panels. Semi-structured interviews were conducted with representatives of clinical laboratories offering hereditary cancer panels via NGS. Several themes emerged from the responses pertaining to hereditary cancer panel development, the importance of communication of panel properties with patients, variant reporting policies, and the future of hereditary cancer gene testing. Clinical utility was discussed as primary consideration during panel development. In addition, while participants indicated gene and syndrome overlap prompted panel development in general, laboratories differed in their opinions of whether phenotypic overlap warrants offering pan-cancer panels only versus cancer specific panels. Participants stressed the importance of patients understanding implications of panel testing, including what is tested for and limitations of testing. While all laboratories discussed the limitations of a variant of uncertain significance result, they differed significantly in their reporting methods. This study provides healthcare providers information on the laboratory approach to panel testing, highlighting both commonalities and differences in laboratory approaches, and may allow providers to make more informed decisions when ordering hereditary cancer panels.

Diagnostic Exome Sequencing Identifies a Novel Gene, EMILIN1, Associated with Autosomal-Dominant Hereditary Connective Tissue Disease.

Heritable connective tissue diseases are a highly heterogeneous family of over 200 disorders that affect the extracellular matrix. While the genetic basis of several disorders is established, the etiology has not been discovered for a large portion of patients, likely due to rare yet undiscovered disease genes. By performing trio-exome sequencing of a 55-year-old male proband presenting with multiple symptoms indicative of a connective disorder, we identified a heterozygous missense alteration in exon 1 of the Elastin Microfibril Interfacer 1 (EMILIN1) gene, c.64G>A (p.A22T). The proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Sanger sequencing confirmed that the EMILIN1 alteration, which maps around the signal peptide cleavage site, segregated with disease in the affected proband, mother, and son. The impaired secretion of EMILIN-1 in cells transfected with the mutant p.A22T coincided with abnormal protein accumulation within the endoplasmic reticulum. In skin biopsy of the proband, we detected less EMILIN-1 with disorganized and abnormal coarse fibrils, aggregated deposits underneath the epidermis basal lamina, and dermal cells apoptosis. These findings collectively suggest that EMILIN1 may represent a new disease gene associated with an autosomal-dominant connective tissue disorder.

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

PURPOSE: Germ-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both well-established, high-risk cancer genes (e.g., BRCA1/2, MLH1, MSH2) as well as more recently identified cancer genes (e.g., PALB2, BRIP1), many of which have increased but less well-defined penetrance. METHODS: Clinical genetic testing was performed on over 10,000 consecutive cases referred for evaluation of germ-line cancer genes, and results were analyzed for frequency of pathogenic or likely pathogenic variants, and were stratified by testing panel, gene, and clinical history. RESULTS: Overall, a molecular diagnosis was made in 9.0% of patients tested, with the highest yield in the Lynch syndrome/colorectal cancer panel. In patients with breast, ovarian, or colon/stomach cancer, positive yields were 9.7, 13.4, and 14.8%, respectively. Approximately half of the pathogenic variants identified in patients with breast or ovarian cancer were in genes other than BRCA1/2. CONCLUSION: The high frequency of positive results in a wide range of cancer genes, including those of high penetrance and with clinical care guidelines, underscores both the genetic heterogeneity of hereditary cancer and the usefulness of multigene panels over genetic tests of one or two genes.Genet Med 18 8, 823-832.

Cancer genetic testing panels for inherited cancer susceptibility: the clinical experience of a large adult genetics practice.

Next-generation sequencing genetic testing panels for cancer susceptibility (cancer panels) have recently become clinically available. At present, clinical utility is unknown and there are no set criteria or guidelines established for whom to offer such testing. Although it may be a cost-effective method to test multiple cancer susceptibility genes concurrently, the rate of finding variants of unknown significance (VUS) may be high and testing may yield mutations in genes with no established management recommendations. We describe our Center's experience over a 14-month period (April 2012-June 2013) for patient interest and uptake in cancer panel testing and whether there were predictors of pursuing testing or identifying mutations. Using a clinical ranking system, patients' family histories were ranked from 0 to 3 (low likelihood to high likelihood for underlying genetic susceptibility). The clinical ranking system was assessed to determine its predictability of finding mutations. Of the 689 patients who met inclusion criteria, the option of pursuing a cancer panel was discussed with 357 patients; 63 (17.6 %) patients pursued testing. Those who pursued testing were more likely to be older, male, affected with cancer, affected with multiple primary cancers, and had a higher clinical rank than non-pursuers. There were no significant predictors of finding a mutation on panel testing. Of the 61 patients who have received results, there was a 6.6 % mutation rate and 19.7 % VUS rate. The yield of cancer panels in clinical practice is low and the strength of family history alone may not predict likelihood of finding a mutation.

Physicians' preparedness for integration of genomic and pharmacogenetic testing into practice within a major healthcare system.

PURPOSE: Physicians will play a large role in the delivery of genomic medicine, given the limited number of trained genetics professionals. The objective of this study was to assess physician preparedness for incorporating genomic testing (GT) and pharmacogenetic testing (PT) into practice by determining knowledge, experience, comfort level, and barriers, as well as their expectations for practice and educational needs. METHODS: A 30-question survey was distributed to physicians spanning all disciplines within our healthcare system. RESULTS: Perceived knowledge was poor; 40%-72% reported "no to minimal knowledge" for all genomics topics. Recent graduates or those with no patients who had undergone GT or PT had lower comfort levels. Participating physicians anticipate usage to increase; however, most were uncertain when and how to incorporate genomics into practice. Physicians perceived lack of knowledge and time to keep updated as their greatest barriers to incorporating GT and PT into practice. CONCLUSION: Overall, physicians appear underprepared, perceiving they lack sufficient knowledge and confidence to incorporate GT and PT into practice. The majority of physicians expect their role in GT and PT to increase. The results underscore the importance of enhancing policies and initiatives to increase physician knowledge and comfort level.

Genetic testing by cancer site: ovary.

Approximately 1 in every 4 to 5 women with a diagnosis of ovarian cancer has a hereditary gene mutation that is responsible for the development of her cancer. Identifying women at increased risk of developing ovarian cancer due to a hereditary cancer syndrome can allow for early detection or prevention of not only ovarian cancer, but also other cancers, depending on the causative gene. This review focuses on 3 of the most common hereditary ovarian cancer syndromes, hereditary breast and ovarian cancer syndrome (the BRCA1 and BRCA2 genes), Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome), and Peutz-Jeghers syndrome, including key features, genetics, and management of these syndromes. In addition, newly discovered genes (eg, RAD51C and RAD51D) linked to ovarian cancer are discussed.

Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline.

Identifying individuals who have Lynch syndrome (LS) involves a complex diagnostic work up that includes taking a detailed family history and a combination of various genetic and immunohistochemical tests. The National Society of Genetic Counselors (NSGC) and the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC) have come together to publish this clinical practice testing guideline for the evaluation of LS. The purpose of this practice guideline is to provide guidance and a testing algorithm for LS as well as recommendations on when to offer testing. This guideline does not replace a consultation with a genetics professional. This guideline includes explanations in support of this and a summary of background data. While this guideline is not intended to serve as a review of LS, it includes a discussion of background information on LS, and cites a number of key publications which should be reviewed for a more in-depth understanding of LS. These guidelines are intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses and other healthcare providers who evaluate patients for LS.

Genetic counseling considerations in the evaluation of families for Lynch syndrome--a review.

Lynch syndrome is the most common hereditary colorectal cancer syndrome and the most common cause of hereditary endometrial cancer. Identifying and evaluating families for Lynch syndrome is increasing in complexity due to the recognition that: family history-based clinical criteria lack sensitivity and specificity; genetic testing for Lynch syndrome continues to evolve as understanding of the molecular mechanisms underlying it evolves; and the Lynch syndrome phenotype encompasses multiple organ systems and demonstrates overlap with other hereditary cancer syndromes. This document is a summary of considerations when evaluating individuals and families for Lynch syndrome, including information on cancer risks, diagnostic criteria, tumor and genetic testing strategies, and the management of individuals with this condition.

Detection of BRCA1 and BRCA2 Ashkenazi Jewish founder mutations in formalin-fixed paraffin-embedded tissues using conventional PCR and heteroduplex/amplicon size differences.

In many families with histories suggestive of BRCA1- or BRCA2-related disease, the proband is deceased. Reliable assessment of archived tissue blocks not amenable to full gene sequencing would be helpful. In this study, a polymerase chain reaction (PCR) assay using primers that bracket the BRCA mutation site and microfluidics-based detection of heteroduplex/amplicon size differences was developed to circumvent artifacts associated with low quality DNA from formalin-fixed paraffin-embedded (FFPE) tissue. Genomic DNA was extracted from 100 FFPE specimens from patients that had previously undergone BRCA gene sequence analysis on blood specimens. Conventional PCR amplification products were differentiated using the Agilent 2100 Bioanalyzer. One FFPE specimen failed to amplify the wild-type alleles for all three sites and was therefore called indeterminate. All 62 FFPE specimens with known Ashkenazi Jewish founder mutations had both the wild-type and the correct mutated allele amplified, including one specimen that failed to amplify the mutant allele in other real-time PCR assays. Appropriately, 21 FFPE specimens known to have other BRCA1/2 mutations and 16 without any mutation had only the wild-type allele correctly amplified for each target. Therefore, by changing the primer location and detecting amplicons via heteroduplexes formed by size differences, we identified mutations from FFPE tissues missed using real-time methods.