Challenges and Errors in Genetic Testing: The Fifth Case Series.

PURPOSE: In this ongoing case series, 33 genetic testing cases are documented in which tests were recommended, ordered, interpreted, or used incorrectly and/or in which clinicians faced challenges related to history/reports provided by patients or laboratories. METHODS: An invitation to submit cases of challenges or errors in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, as part of a case series with Precision Oncology News, and via social media (i.e., Facebook, Twitter, LinkedIn). Deidentified clinical documentation was requested and reviewed when available. Thirty-three cases were submitted, reviewed, and accepted. A thematic analysis was performed. Submitters were asked to approve cases before submission. RESULTS: All cases took place in the United States, involved hereditary cancer testing and/or findings in cancer predisposition genes, and involved medical-grade genetic testing, direct-to-consumer testing, or research genetic testing. In 9 cases, test results were misinterpreted, leading to incorrect screening or risk-reducing procedures being performed/recommended. In 5 cases, incorrect or unnecessary testing was ordered/recommended. In 3 cases, incorrect clinical diagnoses were made, or opportunities for diagnoses were delayed. In 3 cases, errors or challenges arose related to medical intervention after testing or reported genetic diagnosis. In 2 cases, physicians provided incorrect information related to the inheritance pattern of a syndrome. In 2 cases, there were challenges related to the interpretation of genetic variants. In 2 cases, challenges arose after direct-to-consumer testing. One case involved test results that should never have been reported based on sample quality. In 1 case, a patient presented a falsified test result. In 5 cases, multiple errors were made. DISCUSSION: As genetic testing continues to become more complicated and common, it is critical that patients and nongenetics providers have access to accurate and timely genetic counseling information. Even as multiple medical bodies highlight the value of genetic counselors (GCs), tension exists in the genomics community as GCs work toward licensure and Medicare provider status. It is critical that health care communities leverage, rather than restrict, the expertise and experience of GCs so that patients can benefit from, and not be harmed by, genetic testing. In order to responsibly democratize genomics, it will be important for genetics and nongenetic health care providers to collaborate and use alternative service delivery models and technology solutions at point of care. To deliver on the promise of precision medicine, accurate resources and tools must be utilized.

IMProving care After inherited Cancer Testing (IMPACT) study: protocol of a randomized trial evaluating the efficacy of two interventions designed to improve cancer risk management and family communication of genetic test results.

BACKGROUND: Implementing genetic testing for inherited cancer predisposition into routine clinical care offers a tremendous opportunity for cancer prevention and early detection. However, genetic testing itself does not improve outcomes; rather, outcomes depend on implemented follow-up care. The IMPACT study is a hybrid type I randomized effectiveness-implementation trial to simultaneously evaluate the effectiveness of two interventions for individuals with inherited cancer predisposition focused on: 1) increasing family communication (FC) of genetic test results; and 2) improving engagement with guideline-based cancer risk management (CRM). METHODS: This prospective study will recruit a racially, geographically, and socioeconomically diverse population of individuals with a documented pathogenic/likely pathogenic (P/LP) variant in an inherited cancer gene. Eligible participants will be asked to complete an initial trial survey and randomly assigned to one of three arms: A) GeneSHARE, a website designed to increase FC of genetic test results; B) My Gene Counsel's Living Lab Report, a digital tool designed to improve understanding of genetic test results and next steps, including CRM guidelines; or C) a control arm in which participants continue receiving standard care. Follow-up surveys will be conducted at 1, 3, and 12 months following randomization. These surveys include single-item measures, scales, and indices related to: 1) FC and CRM behaviors and behavioral factors following the COM-B theoretical framework (i.e., capability, opportunity, and motivation); 2) implementation outcomes (i.e., acceptability, appropriateness, exposure, and reach); and 3) other contextual factors (i.e., sociodemographic and clinical factors, and uncertainty, distress, and positive aspects of genetic test results). The primary outcomes are an increase in FC of genetic test results (Arm A) and improved engagement with guideline-based CRM without overtreatment or undertreatment (Arm B) by the 12-month follow-up survey. DISCUSSION: Our interventions are designed to shift the paradigm by which individuals with P/LP variants in inherited cancer genes are provided with information to enhance FC of genetic test results and engagement with guideline-based CRM. The information gathered through evaluating the effectiveness and implementation of these real-world approaches is needed to modify and scale up adaptive, stepped interventions that have the potential to maximize FC and CRM. TRIAL REGISTRATION: This study is registered at Clinicaltrials.gov (NCT04763915, date registered: February 21, 2021). PROTOCOL VERSION: September 17th, 2021 Amendment Number 04.

Adverse Events in Genetic Testing: The Fourth Case Series.

PURPOSE: In this ongoing national case series, we document 25 new genetic testing cases in which tests were recommended, ordered, interpreted, or used incorrectly. METHODS: An invitation to submit cases of adverse events in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, private genetic counselor laboratory groups, and via social media platforms (i.e., Facebook, Twitter, LinkedIn). Examples highlighted in the invitation included errors in ordering, counseling, and/or interpretation of genetic testing and did not limit submissions to cases involving genetic testing for hereditary cancer predisposition. Clinical documentation, including pedigree, was requested. Twenty-six cases were accepted, and a thematic analysis was performed. Submitters were asked to approve the representation of their cases before manuscript submission. RESULTS: All submitted cases took place in the United States and were from cancer, pediatric, preconception, and general adult settings and involved both medical-grade and direct-to-consumer genetic testing with raw data analysis. In 8 cases, providers ordered the wrong genetic test. In 2 cases, multiple errors were made when genetic testing was ordered. In 3 cases, patients received incorrect information from providers because genetic test results were misinterpreted or because of limitations in the provider's knowledge of genetics. In 3 cases, pathogenic genetic variants identified were incorrectly assumed to completely explain the suspicious family histories of cancer. In 2 cases, patients received inadequate or no information with respect to genetic test results. In 2 cases, result interpretation/documentation by the testing laboratories was erroneous. In 2 cases, genetic counselors reinterpreted the results of people who had undergone direct-to-consumer genetic testing and/or clarifying medical-grade testing was ordered. DISCUSSION: As genetic testing continues to become more common and complex, it is clear that we must ensure that appropriate testing is ordered and that results are interpreted and used correctly. Access to certified genetic counselors continues to be an issue for some because of workforce limitations. Potential solutions involve action on multiple fronts: new genetic counseling delivery models, expanding the genetic counseling workforce, improving genetics and genomics education of nongenetics health care professionals, addressing health care policy barriers, and more. Genetic counselors have also positioned themselves in new roles to help patients and consumers as well as health care providers, systems, and payers adapt to new genetic testing technologies and models. The work to be done is significant, but so are the consequences of errors in genetic testing.

Correction to: Talking with Children about Adult-Onset Hereditary Cancer Risk: A Developmental Approach for Parents.

The original article [1] was initially published with the following list of authors: Allison Werner-Lin, Shana L. Merrill, and Amanda C. Brandt. This author list is now corrected as follows: Allison Werner-Lin, Shana L. Merrill, Amanda C. Brandt, Rachel E. Barnett, & Ellen T. Matloff.

Talking with Children About Adult-Onset Hereditary Cancer Risk: A Developmental Approach for Parents.

Families often express difficulty to their providers and request guidance regarding the task of communicating with children about potential adult-onset inherited cancer risks. This disclosure is often complicated by the parent's ongoing adjustment to their mutation status, guilt at potential transmission of the mutation to the child, concern over inciting distress in children, and the varied capacities of children in the home to understand genetic information. Providers often do not have adequate resources to support or facilitate disclosure of genetic test results to children. Optimally, communication about inherited cancer risk is an open, ongoing process within the family. We recommend that parents tailor conversations to the child's developmental, cognitive, emotional, and behavioral abilities to support comprehension. Based on well-established theories of child development, empirical research on family communication of hereditary cancer risk, and clinical counseling experience, we offer recommendations for parental disclosure of genetic risk to children, case examples with critical discussion of relevant topics, common child questions with sample scripted responses, and additional printed and online resources.

Challenges in Interpreting Germline Mutations in BARD1 and ATM in Breast and Ovarian Cancer Patients.

Next-generation sequencing promotes identification of mutations in non-BRCA1/2 genes in hereditary cancer families. The contribution of mutations in moderate penetrance genes to hereditary cancer risk is not well established. Here, we report a family with early onset breast and fallopian tube cancer that was identified as carrying germline mutations in BARD1 and ATM genes. Loss of heterozygosity studies suggest a causative role of the BARD1 mutation in the development of primary peritoneal cancer, but fail to confirm an association between germline ATM mutations and breast cancer development in this family. Complexities in interpreting implications of mutations in moderate-risk cancer susceptibility genes are discussed.

Defining the polyposis/colorectal cancer phenotype associated with the Ashkenazi GREM1 duplication: counselling and management recommendations.

Hereditary mixed polyposis is a genetically heterogeneous, autosomal dominant condition with adenomatous, hyperplastic and juvenile polyps. We conducted a comprehensive clinical evaluation of a large Ashkenazi Jewish family with this phenotype and performed extensive genetic testing. As seen in one previous report, a 40 kb duplication upstream of GREM1 segregated with the polyposis/colon cancer phenotype in this kindred. Our study confirms the association of GREM1 with mixed polyposis and further defines the phenotype seen with this mutation. This gene should be included in the test panel for all Jewish patients with mixed polyposis and may be considered in any Ashkenazi patient with unexplained hereditary colon cancer when mutations in other hereditary colon cancer genes have been ruled out.

Testing for Hereditary Breast Cancer: Panel or Targeted Testing? Experience from a Clinical Cancer Genetics Practice.

Approaches to hereditary breast cancer testing are shifting as multi-gene panels become more widely available. This paper describes our center's experience and outcomes of a 6-gene panel test as a first-tier approach in patients who were candidates for BRCA testing. Between July and December 2013, a 6-gene panel test was ordered for patients meeting criteria for BRCA testing. A retrospective review detailed the mutation and variant of uncertain significance (VUS) rates for the genes analyzed. The mutation rate was 5.2 % (n = 7) and the VUS rate was 6.7 % (n = 9). A subsequent review determined the number of BRCA-negative patients who would have been offered additional single gene testing had BRCA, only, been their first-tier test. Applying consensus criteria revealed 7.1 % (n = 9) cases that met criteria for additional testing. Pedigree analysis by a certified genetic counselor revealed 26.8 % (n = 34) cases that would have been offered additional testing based on personal and/or family history. Our results suggest that this panel may be warranted as a first-tier test for a small subset of patients, but likely represents over testing for the majority of patients who are candidates for BRCA testing. The genes selected for panels, the extra costs per patient and the chance of VUS must be considered before we uniformly switch from BRCA to full panel testing on all patients.

Erratum to: Changes in specialists' perspectives on cancer genetic testing, prophylactic surgery and insurance discrimination: then and now.

Erratum to: J Genet Counsel DOI 10.1007/s10897-013-9625-z . In the "Funding" section, the company HRA was incorrectly referred to as HSR. The full name of the company is "HRA­ Healthcare Research & Analytics."

Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers.

Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan-Meier analyses. Use of RRSO was 45% for BRCA1 and 34% for BRCA2 by age 40, and 86% for BRCA1 and 71% for BRCA2 by age 50. RRM usage was estimated to be 46% by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers underwent RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced the use of RRSO and RRM in both BRCA1 and BRCA2. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO.

Adverse events in cancer genetic testing: the third case series.

After repeated media attention in 2013 due to the Angelina Jolie disclosure and the Supreme Court decision to ban gene patents, the demand for cancer genetic counseling and testing services has never been greater. Debate has arisen regarding who should provide such services and the quality of genetics services being offered. In this ongoing case series, we document 35 new cases from 7 states (California, Connecticut, Florida, Georgia, Missouri, Pennsylvania, and Utah) and the District of Columbia of adverse outcomes in cancer genetic testing when performed without the involvement of a certified genetic counselor. We identified 3 major themes of errors: wrong genetic tests ordered, genetic test results misinterpreted, and inadequate genetic counseling. Patient morbidity and mortality were an issue in several of these cases. The complexity of cancer genetic testing and counseling has grown exponentially with the advent of multigene panels that include rare genes and the potential for more variants of uncertain significance. We conclude that genetic counseling and testing should be offered by certified genetics providers to minimize the risks, maximize the benefits, and utilize health care dollars most efficiently.

"Would you test your children without their consent?" and other sticky dilemmas in the field of cancer genetic testing.

Cancer genetic testing is surrounded by myriad ethical, legal, and psychosocial implications which are being revisited as testing expands into an everyday practice and into more complicated areas like whole exome and direct-to-consumer testing. We chose to survey cancer genetic counselors and physicians from a wide range of non-genetics specialties to determine what they would do if faced with the complex decisions associated with cancer genetic testing, how their views compare, and how they align with current guidelines and data. Genetic counselors were significantly more likely than non-genetics physicians to bill their insurance for testing (94.9 vs. 86.8 %; p = 0.001) and purchase life insurance before testing (86.6 vs. 68.6 %; p = 0.000) and were less likely to use an alias (3.2 vs. 13.2 %; p = 0.000) or order testing on their own DNA (15.3 vs. 24.2 %; p = 0.004). They were also less likely to test their minor children (0.9 vs. 33.1 %; p = 0.000) or test their children without their knowledge and consent/assent (1.4 vs.11.5 %; p = 0.000). The results of our study indicate that there is wide variation regarding what clinicians predict they would do in the areas of ethical, legal and psychosocial issues in cancer genetic testing. Cancer genetic counselors' choices are more aligned with professional guidelines, likely due to their experience in the field and awareness of current guidelines. These data are a starting point for a broader discussion of who should offer cancer genetic counseling and testing to patients, particularly as the complexity of the available testing options and associated issues increase with whole exome sequencing.

Changes in specialists' perspectives on cancer genetic testing, prophylactic surgery and insurance discrimination: then and now.

We surveyed cancer genetics specialists in 1998 to learn what they would do if at 50% risk to carry a BRCA or Lynch syndrome mutation. We chose to repeat our study 14 years later, to examine how perspectives have changed with the extensive data now available. In July 2012 we surveyed the National Society of Genetic Counselors (NSGC) Cancer Special Interest Group via an internet based survey. We found statistically significant increases in the percentage of specialists who: would undergo BRCA testing (p = 0.0006), opt for prophylactic bilateral mastectomy (p =0.0001), opt for prophylactic removal of their uterus and ovaries for Lynch syndrome (p =0.0057 and P = 0.0090, respectively), and bill testing to insurance (p >0.0001). There were also statistically significant decreases in the percentage of participants who would have their colon removed for Lynch syndrome (p = 0.0002) and use an alias when pursuing testing (p > 0.0001). Over the past 14 years there has been a major change in perspective amongst cancer genetic specialists regarding genetic testing, prophylactic surgery and insurance discrimination.

Adverse events in cancer genetic testing: medical, ethical, legal, and financial implications.

Cancer genetic counseling and testing are now integral services in progressive cancer care. There has been much debate over whether these services should be delivered by providers with specialized training in genetics or by all clinicians. Adverse outcomes resulting from cancer genetic counseling and testing performed by clinicians without specialization in genetics have been reported, but formal documentation is sparse. In this review, we present a series of national cases illustrating major patterns of errors in cancer genetic counseling and testing and the resulting impact on medical liability, health care costs, and the patients and their families.

Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers.

PURPOSE: Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. METHODS: Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. RESULTS: Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups. CONCLUSION: Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.

What I wish I'd known before surgery: BRCA carriers' perspectives after bilateral salipingo-oophorectomy.

We retrospectively studied BRCA carriers with a history of prophylactic bilateral salingo-oophorectomy (PBSO) regarding: (1) their post-operative symptoms, (2) their recollection of pre-operative conversations with their health care providers regarding possible surgical side-effects and (3) what information they would have found helpful to have before surgery. Female BRCA carriers seen through the Yale Cancer Genetic Counseling Program who had PBSO were invited to participate in a questionnaire that assessed their recall of information they received pre-operatively compared with their post-operative knowledge and symptoms related to menopause, cognitive changes, loss of fertility, cancer risks, osteoporosis, heart disease, vasomotor symptoms, urogenital symptoms, sexuality and body image. The questionnaire also elicited written feedback from participants regarding their decision to have PBSO, what they wished they had known before surgery, advice for other BRCA carriers considering this surgery and advice for health care providers who counsel women about PBSO. Two hundred and ninety female BRCA carriers were invited to participate and 113 (39.0%) indicated they were interested. Of those, 99 (87.6%) returned their questionnaire and 98 (86.7%) responses were included in the analysis. The mean age at PBSO was 45.5 years (range: 32-63 years). The five most common "frequent" or "very frequent" post-surgical symptoms were: vaginal dryness (52.1%), changes in interest in sex (50.0%), sleep disturbances (46.7%), changes in sex life (43.9) and hot flashes (42.9%). The majority of women would have found it helpful to have more information regarding the impact of this surgery on their sex life (59.2%), the availability of sex counseling (57.1%) and the risk of coronary heart disease (57.1%). This study illustrates that while health care providers are discussing selected side effects of PBSO, women undergoing this surgery have other concerns that should be addressed. This information provides insights into the informational needs of BRCA carriers considering PBSO.