Preparing for the unexpected: Recommendations for returning secondary findings in late-stage cancer care.

PURPOSE: We conducted qualitative interviews with patients with cancer and providers to identify gaps in clinical care and highlight care delivery solutions for the return of secondary germline findings. METHODS: Twelve patients and 19 cancer providers from the United States were interviewed between January 2019 and May 2021. Interviews elicited feedback about patient information needs, emotional responses to secondary findings, and recommendations for improving pre-test education. RESULTS: Patients' responses ranged from gratitude to regret, depending on how much pre-test counseling they received before tumor testing. Providers cited insufficient clinic time as a major barrier to pretest education, favoring online support tools and standardized pre-test education models. Providers had differing perspectives on how pre-test education should be integrated into clinical workflows but agreed that it should include the differences between somatic and germline testing, the likelihood of medically actionable findings, and the possibility of being referred to a genetics provider. CONCLUSION: The spectrum of participants' responses to their secondary findings underscores the importance of adequate pre-test discussions before somatic sequencing. Although educational interventions could address patients' information needs and augment traditional pre-test counseling, health care systems, labs, and genetic providers may be called on to play greater roles in pre-test education.

Private Payer and Medicare Coverage Policies for Use of Circulating Tumor DNA Tests in Cancer Diagnostics and Treatment.

BACKGROUND: Circulating tumor DNA (ctDNA) is used to select initial targeted therapy, identify mechanisms of therapeutic resistance, and measure minimal residual disease (MRD) after treatment. Our objective was to review private and Medicare coverage policies for ctDNA testing. METHODS: Policy Reporter was used to identify coverage policies (as of February 2022) from private payers and Medicare Local Coverage Determinations (LCDs) for ctDNA tests. We abstracted data regarding policy existence, ctDNA test coverage, cancer types covered, and clinical indications. Descriptive analyses were performed by payer, clinical indication, and cancer type. RESULTS: A total of 71 of 1,066 total policies met study inclusion criteria, of which 57 were private policies and 14 were Medicare LCDs; 70% of private policies and 100% of Medicare LCDs covered at least one indication. Among 57 private policies, 89% specified a policy for at least 1 clinical indication, with coverage for ctDNA for initial treatment selection most common (69%). Of 40 policies addressing progression, coverage was provided 28% of the time, and of 20 policies addressing MRD, coverage was provided 65% of the time. Non-small cell lung cancer (NSCLC) was the cancer type most frequently covered for initial treatment (47%) and progression (60%). Among policies with ctDNA coverage, coverage was restricted to patients without available tissue or in whom biopsy was contraindicated in 91% of policies. MRD was commonly covered for hematologic malignancies (30%) and NSCLC (25%). Of the 14 Medicare LCD policies, 64% provided coverage for initial treatment selection and progression, and 36% for MRD. CONCLUSIONS: Some private payers and Medicare LCDs provide coverage for ctDNA testing. Private payers frequently cover testing for initial treatment, especially for NSCLC, when tissue is insufficient or biopsy is contraindicated. Coverage remains variable across payers, clinical indications, and cancer types despite inclusion in clinical guidelines, which could impact delivery of effective cancer care.

Germline mutations and age at onset of lung adenocarcinoma.

BACKGROUND: To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset. METHODS: The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non-FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model. RESULTS: Subjects (n = 187; age, 28-89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack-years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5-20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5-16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, -1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking. CONCLUSIONS: Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high-risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis.

Recall of Genomic Testing Results Among Patients with Cancer.

BACKGROUND: Genomic testing of somatic and germline DNA has transformed cancer care. However, low genetic knowledge among patients may compromise care and health outcomes. Given the rise in genomic testing, we sought to understand patients' knowledge of their genetic test results. MATERIALS AND METHODS: We conducted a survey-based study with 85 patients at a comprehensive cancer center. We compared self-reported recall of (a) having had somatic/germline testing and (b) their specific somatic/germline results to the genomic test results documented in the medical record. RESULTS: Approximately 30% of patients did not recall having had testing. Of those who recalled having testing, 44% of patients with pathogenic/likely pathogenic germline mutations and 57% of patients with reported somatic alterations did not accurately recall their specific gene or variant-level results. CONCLUSION: Given significant knowledge gaps in patients' recall of genomic testing, there is a critical need to improve patient-directed education and return-of-results strategies.

Oncologists' perceptions of the usefulness of cancer survivorship care plan components.

PURPOSE: The Institute of Medicine recommends that cancer patients receive survivorship care plans (SCP) summarizing information important to the individual's long-term care. The various components of SCPs have varying levels of evidence supporting their impact. We surveyed medical oncologists to better understand how they perceived the relative value of different SCP components. METHODS: Medical oncologists caring for patients in diverse US practice settings were surveyed (357 respondents; participation rate 52.9%) about their perceptions of the usefulness of various components of SCPs to both patients and primary care physicians (PCPs). RESULTS: Oncologists perceived treatment summaries as "very useful" for PCPs but were less likely to perceive them as "very useful" for patients (55% vs. 40%, p < 0.001). Information about the psychological effects of cancer (41% vs. 29%; p < 0.001) and healthy behaviors (67% vs. 41%; p < 0.001) were considered more useful to patients than to PCPs. From 3 to 20% of oncologists believed that any given component of the SCP was not useful to either PCPs or patients. Oncologists who perceived SCPs to be more useful tended to be female or to practice in settings with a fully implemented electronic health record. CONCLUSIONS: Oncologists do not perceive all components of SCPs to be equally useful to both patients and PCPs. To be successfully implemented, the SCP should be efficiently tailored to the unique needs and knowledge of patients and their PCPs. A minority of oncologists appear to be late adopters, suggesting that some resistance to the adoption of SCPs remains.

Demystifying the estimand framework: a case study using patient-reported outcomes in oncology.

Patient-reported outcome (PRO) measures describe how a patient feels or functions and are increasingly being used in benefit-risk assessments in the development of cancer drugs. However, PRO research objectives are often ill-defined in clinical cancer trials, which can lead to misleading conclusions about patient experiences. The estimand framework is a structured approach to aligning a clinical trial objective with the study design, including endpoints and analysis. The estimand framework uses a multidisciplinary approach and can improve design, analysis, and interpretation of PRO results. On the basis of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E9(R1) addendum, we provide an overview of the estimand framework intended for a multistakeholder audience. We apply the estimand framework to a hypothetical trial for breast cancer, using physical function to develop specific PRO research objectives. This Policy Review is not an endorsement of a specific study design or outcome; rather, it is meant to show the application of principles of the estimand framework to research study design and add to ongoing discussion. Use of the estimand framework to review medical products and label PROs in oncology can improve communication between stakeholders and ultimately provide a clearer interpretation of patient experience in the development of oncological drugs.

Factors influencing cancer genetic somatic mutation test ordering by cancer physician.

BACKGROUND: Clinical whole exome sequencing was introduced in an Australian centre in 2017, as an alternative to Sanger sequencing. We aimed to identify predictors of cancer physicians' somatic mutation test ordering behaviour. METHODS: A validated instrument assessed somatic mutation test ordering, genomic confidence, perceived utility of tumour molecular profiling, and percent of patients eligible for targeted therapy. A cash incentive was included in 189/244 questionnaires which were mailed to all Queensland cancer specialists in November 2018. RESULTS: 110 participated (response rate 45%); 54.7% oncologists, and the remainder were surgeons, haematologists and pulmonologists. Oncologists were more likely to respond (p = 0.008), and cash incentive improved the response rate (p < 0.001). 67/102 (65.7%) of physicians ordered ≥ 5 somatic mutation tests annually. Oncologists saw 86.75 unique patients monthly and ordered 2.33 somatic mutation tests (2.2%). An average of 51/110 (46.1%) reported having little/no genomic confidence. Logistic regression identified two significant predictors of somatic mutation test ordering: being an oncologist (OR 3.557, CI 1.338-9.456; p = 0.011) and having greater confidence in interpreting somatic results (OR 5.926, CI 2.230-15.74; p < 0.0001). CONCLUSIONS: Consistent with previous studies, the majority of cancer physicians ordered somatic mutation tests. However, the percentage of patients on whom tests were ordered was low. Almost half respondents reported low genomic confidence. Somatic mutation test ordering was higher amongst oncologists and those with increased confidence in interpreting somatic variants. It is unclear whether genomically confident individuals ordered more tests or whether ordering more tests increased genomic confidence. Educational interventions could improve confidence and enhance test ordering behaviour.

Private Payer and Medicare Coverage for Circulating Tumor DNA Testing: A Historical Analysis of Coverage Policies From 2015 to 2019.

BACKGROUND: Clinical adoption of the sequencing of circulating tumor DNA (ctDNA) for cancer has rapidly increased in recent years. This sequencing is used to select targeted therapy and monitor nonresponding or progressive tumors to identify mechanisms of therapeutic resistance. Our study objective was to review available coverage policies for cancer ctDNA-based testing panels to examine trends from 2015 to 2019. METHODS: We analyzed publicly available private payer policies and Medicare national coverage determinations and local coverage determinations (LCDs) for ctDNA-based panel tests for cancer. We coded variables for each year representing policy existence, covered clinical scenario, and specific ctDNA test covered. Descriptive analyses were performed. RESULTS: We found that 38% of private payer coverage policies provided coverage of ctDNA-based panel testing as of July 2019. Most private payer policy coverage was highly specific: 87% for non-small cell lung cancer, 47% for EGFR gene testing, and 79% for specific brand-name tests. There were 8 final, 2 draft, and 2 future effective final LCDs (February 3 and March 15, 2020) that covered non-FDA-approved ctDNA-based tests. The draft and future effective LCDs were the first policies to cover pan-cancer use. CONCLUSIONS: Coverage of ctDNA-based panel testing for cancer indications increased from 2015 to 2019. The trend in private payer and Medicare coverage is an increasing number of coverage policies, number of positive policies, and scope of coverage. We found that Medicare coverage policies are evolving to pan-cancer uses, signifying a significant shift in coverage frameworks. Given that genomic medicine is rapidly changing, payers and policymakers (eg, guideline developers) will need to continue to evolve policies to keep pace with emerging science and standards in clinical care.

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

Psychological outcomes related to exome and genome sequencing result disclosure: a meta-analysis of seven Clinical Sequencing Exploratory Research (CSER) Consortium studies.

PURPOSE: As exome and genome sequencing (ES/GS) enters the clinic, there is an urgent need to understand the psychological effects of test result disclosure. Through a Clinical Sequencing Exploratory Research (CSER), phase 1 (CSER1) Consortium collaboration, we evaluated participants' psychological outcomes across multiple clinical settings. METHODS: We conducted a random effects meta-analysis of state anxiety (Hospital Anxiety and Depression Scale [HADS]/Generalized Anxiety Disorder 7-item), depressive symptoms (HADS/Personal Health Questionnaire 9-item), and multidimensional impact (i.e., test-related distress, uncertainty and positive impact: modified Multidimensional Impact of Cancer Risk Assessment/Feelings About Genomic Testing Results scale). RESULTS: Anxiety and depression did not increase significantly following test result disclosure. Meta-analyses examining mean differences from pre- to postdisclosure revealed an overall trend for a decrease in participants' anxiety. We observed low levels of test-related distress and perceptions of uncertainty in some populations (e.g., pediatric patients) and a wide range of positive responses. CONCLUSION: Our findings across multiple clinical settings suggest no clinically significant psychological harms from the return of ES/GS results. Some populations may experience low levels of test-related distress or greater positive psychological effects. Future research should further investigate the reasons for test-related psychological response variation.

Influence of Peer Physicians on Intensity of End-of-Life Care for Cancer Decedents.

BACKGROUND: The intensity of end-of-life care varies substantially both within and between areas. Differing practice patterns of individual physicians are likely influenced by their peers. OBJECTIVE: To assess whether intensity of end-of-life care previously provided by a physician's peers influences patterns of care at the end-of-life for that physician's patients. RESEARCH DESIGN: Observational study. SUBJECTS: A total of 185,947 fee-for-service Medicare enrollees with cancer who died during 2006-2010 who were treated by 26,383 physicians. MEASURES: Spending in the last month of life, >1 emergency room visit, >1 hospitalization, intensive care unit admission in the last month of life, chemotherapy within 2 weeks of death, no/late hospice, terminal hospitalization. RESULTS: Mean (SD) spending in the last month of life was $16,237 ($17,124). For each additional $1000 of spending for a peer physician's patients in the prior year, spending for the ego physician's patients was $83 higher (P<0.001). Among physicians with peers both in and out of their practice, more of the peer effect was explained by physicians outside of the practice ($72 increase for each $1000 increase by peer physicians' patients, P<0.001) than peer physicians in the practice ($27 for each $1000 increase by within-practice peer physicians' patients, P=0.01). Results were similar across the other measures of end-of-life care intensity. CONCLUSIONS: Physician's peers exert influence on the intensity of care delivered to that physician's patients at the end-of-life. Physician education efforts led by influential providers and provider organizations may have potential to improve the delivery of high-value end-of-life care.

Cancer drug shortages: Awareness and perspectives from a representative sample of the US population.

BACKGROUND: Although cancer drug shortages are a persistent problem in oncology, little is known about the awareness and perspectives of the US population with respect to shortages. METHODS: In 2016, we administered a 13-item cross-sectional survey to 420 respondents who were randomly selected from an online, probability-based sample demographically representative of the adult US population with respect to sex, age, race/ethnicity, education, geography, and income. Analyses applied poststratification sampling weights to draw national inferences. RESULTS: Overall, 16% of respondents reported being aware of drug shortages. Those with a personal history of cancer were more likely to be aware (31% vs 14% [P = .03]). In the overall cohort, most reported wanting to be informed about a substitution due to shortage: 87% and 82% for major or minor differences in efficacy, and 87% and 83% for major or minor differences in side effects. Most also reported they would transfer care to avoid a substitution: 72% for major differences in efficacy, and 61% for major differences in side effects. Black respondents, the uninsured, the unemployed, those with lower income, and the less well-educated were all less likely to report that they would transfer care to avoid major differences in efficacy (all P < .05). CONCLUSION: These data suggest that the US population is largely unaware of cancer drug shortages. Moreover, if being treated for cancer, most people would want to know about drug substitutions, even if it were to result in only minor differences in efficacy or side effects. With more significant differences, many would transfer care. Cancer 2018;124:2205-11. © 2018 American Cancer Society.

Return of genomic results to research participants: the floor, the ceiling, and the choices in between.

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.

Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study.

PURPOSE: Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care. METHODS: One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples. Somatic and germ-line alterations were ranked according to therapeutic or clinical relevance. Results were interpreted using an integrated somatic and germ-line framework and returned in accordance with patient preferences. RESULTS: At the time of this analysis, WES had been performed and results returned to the clinical team for 165 participants. Of 768 curated somatic alterations, only 31% were associated with clinical evidence and 69% with preclinical or inferential evidence. Of 806 curated germ-line variants, 5% were clinically relevant and 56% were classified as variants of unknown significance. The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach. CONCLUSION: The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017.

Oncologists' and cancer patients' views on whole-exome sequencing and incidental findings: results from the CanSeq study.

PURPOSE: Although targeted sequencing improves outcomes for many cancer patients, it remains uncertain how somatic and germ-line whole-exome sequencing (WES) will integrate into care. METHODS: We conducted surveys and interviews within a study of WES integration at an academic center to determine oncologists' attitudes about WES and to identify lung and colorectal cancer patients' preferences for learning WES findings. RESULTS: One-hundred sixty-seven patients (85% white, 58% female, mean age 60) and 27 oncologists (22% female) participated. Although oncologists had extensive experience ordering somatic tests (median 100/year), they had little experience ordering germ-line tests. Oncologists intended to disclose most WES results to patients but anticipated numerous challenges in using WES. Patients had moderately low levels of genetic knowledge (mean 4 correct out of 7). Most patients chose to learn results that could help select a clinical trial, pharmacogenetic and positive prognostic results, and results suggesting inherited predisposition to cancer and treatable noncancer conditions (all ≥95%). Fewer chose to receive negative prognostic results (84%) and results suggesting predisposition to untreatable noncancer conditions (85%). CONCLUSION: The majority of patients want most cancer-related and incidental WES results. Patients' low levels of genetic knowledge and oncologists' inexperience with large-scale sequencing present challenges to implementing paired WES in practice.Genet Med 18 10, 1011-1019.

Pediatric Oncology Provider Views on Performing a Biopsy of Solid Tumors in Children with Relapsed or Refractory Disease for the Purpose of Genomic Profiling.

BACKGROUND: Patients with relapsed and refractory solid tumors have a poor prognosis. Recent advances in genomic technology have made it feasible to screen tumors for actionable mutations, with the anticipation that this may provide benefit to patients. METHODS: Pediatric oncologists were emailed an anonymous 34-question survey assessing their willingness to offer a rebiopsy to patients with relapsed disease for the purpose of tumor genomic profiling. They were presented with two scenarios evaluating morbidity and invasiveness of the procedures using the clinical examples of medulloblastoma and Ewing sarcoma. RESULTS: A total of 195 pediatric oncologists responded to the questionnaire. Morbidity and invasiveness of the procedure demonstrated significant differences in provider willingness to refer their patients for rebiopsy. The pretest probability was a major variable influencing provider willingness to offer a rebiopsy. Respondents were more likely to offer a rebiopsy if the likelihood was high that the results would have an impact on clinical management than if the biopsy was for histologic confirmation alone (mean 89 vs. 56 %; p = 0.017). Compared with the rate of a rebiopsy for histologic confirmation, significantly fewer providers were willing to offer a rebiopsy if they were led to believe the likelihood of finding an actionable mutation was low (mean 45 vs. 56 %; p = 0.021). CONCLUSION: The scenario showed that the pretest probability of finding an actionable mutation was influential in determining provider willingness to offer a rebiopsy for the purpose of tumor genomic profiling. Further research is warranted to evaluate the benefit of tumor genomic profiling in terms of patient outcomes.

Social and behavioral research in genomic sequencing: approaches from the Clinical Sequencing Exploratory Research Consortium Outcomes and Measures Working Group.

The routine use of genomic sequencing in clinical medicine has the potential to dramatically alter patient care and medical outcomes. To fully understand the psychosocial and behavioral impact of sequencing integration into clinical practice, it is imperative that we identify the factors that influence sequencing-related decision making and patient outcomes. In an effort to develop a collaborative and conceptually grounded approach to studying sequencing adoption, members of the National Human Genome Research Institute's Clinical Sequencing Exploratory Research Consortium formed the Outcomes and Measures Working Group. Here we highlight the priority areas of investigation and psychosocial and behavioral outcomes identified by the Working Group. We also review some of the anticipated challenges to measurement in social and behavioral research related to genomic sequencing; opportunities for instrument development; and the importance of qualitative, quantitative, and mixed-method approaches. This work represents the early, shared efforts of multiple research teams as we strive to understand individuals' experiences with genomic sequencing. The resulting body of knowledge will guide recommendations for the optimal use of sequencing in clinical practice.

Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium.

As genomic and exomic testing expands in both the research and clinical arenas, determining whether, how, and which incidental findings to return to the ordering clinician and patient becomes increasingly important. Although opinion is varied on what should be returned to consenting patients or research participants, most experts agree that return of medically actionable results should be considered. There is insufficient evidence to fully inform evidence-based clinical practice guidelines regarding return of results from genome-scale sequencing, and thus generation of such evidence is imperative, given the rapidity with which genome-scale diagnostic tests are being incorporated into clinical care. We present an overview of the approaches to incidental findings by members of the Clinical Sequencing Exploratory Research network, funded by the National Human Genome Research Institute, to generate discussion of these approaches by the clinical genomics community. We also report specific lists of "medically actionable" genes that have been generated by a subset of investigators in order to explore what types of findings have been included or excluded in various contexts. A discussion of the general principles regarding reporting of novel variants, challenging cases (genes for which consensus was difficult to achieve across Clinical Sequencing Exploratory Research network sites), solicitation of preferences from participants regarding return of incidental findings, and the timing and context of return of incidental findings are provided.Genet Med 15 11, 860-867.Genetics in Medicine (2013); 15 11, 860-867. doi:10.1038/gim.2013.133.