Testing For Cancer Predisposition Research Articles

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate.

Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. CHEK2 mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline CHEK2 variants, we review the current knowledge related to the structure of the CHEK2 gene, the function of CHK2 kinase, and the clinical significance of CHEK2 germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.

To test or not to test: genetic cancer predisposition testing in paediatric patients with cancer

Genetic cancer predisposition testing in the paediatric population poses unique ethical dilemmas. Using the hypothetical example of a teenager with cancer with a high probability of having an underlying cancer...

Autonomy and social influence in predictive genetic testing decision‐making: A qualitative interview study

Beauchamp and Childress' definition of autonomous decision-making includes the conditions of intentionality, understanding, and non-control. In genetics, however, a relational conception of autonomy has been increasingly recognized. This article aims to empirically assess aspects of social influence in genetic testing decision-making and to connect these with principlist and relational theories of autonomy. We interviewed 18 adult genetic counsellees without capacity issues considering predictive genetic testing for cancer predisposition for themselves and two counselling physicians in Switzerland. We conducted a qualitative analysis, building on a grounded theory study about predictive genetic testing decision-making. We found that some participants agreed to predictive genetic testing predominantly because relatives wanted them to do it, with some even acting contrary to their own convictions. Others, in contrast, based their decision on purely individualistic reasons but expressed difficulties in explaining their decision to their social environment. Healthcare professionals had a critical influence on decision-making in many cases without being manipulative, as perceived by counsellees. Still, cases of coercion and social pressure occurred within social relationships. In conclusion, predictive genetic testing decision-making includes relational and individualistic aspects, and both are compatible with autonomous decision-making. While the principlist and relational notions of autonomy compete on a theoretical level, they are two sides of the same coin when used as analytical lenses for genetic testing decision-making. Social acceptance of refusal of testing should be improved to mitigate social pressure. Individuals should be encouraged to decide for themselves how much their social environment influences their decision regarding predictive genetic testing.

Examining information-seeking behavior in genetic testing for cancer predisposition: A qualitative interview study

ObjectiveThis study aims to assess information needs and information sources and seeks to illustrate what at-risk individuals consider motivators of and barriers to information-seeking before and after genetic testing for cancer predisposition. MethodsSemi-structured interviews with people seeking genetic counseling in Switzerland were analyzed qualitatively using thematic analysis. Wilson's model of information behavior was the theoretical framework. ResultsWe identified four themes that illustrate motivators of and barriers to information-seeking: attitudes and emotions; knowledge; social environment; and demographic factors. We also elucidated information needs and collected participants' information sources. ConclusionThis study£s empirical approach helps healthcare professionals to understand their patients' behaviors and wishes concerning information-seeking more concretely than theoretical models alone. The study also identifies information gaps, especially outside the genetic counseling setting. Practice implicationsGenetic counselors and other healthcare professionals need to purposefully assist patients in finding trustworthy and accessible information. Healthcare professionals in all disciplines need to be educated about predictive genetic testing.

Paired tumor sequencing and germline testing in breast cancer management: An experience of a single academic center.

BackgroundGenetic testing for cancer predisposition is recommended to women with breast cancer who meet the criteria for such testing. After the FDA approvals of the poly ADP ribose polymerase (PARP) inhibitors, olaparib and talazoparib, for treatment of metastatic breast cancer, carrying germline mutations in BRCA1 and BRCA2 genes, the genetic testing result has become critical in their care. With the recent FDA approval of alpelisib for the treatment of PIK3CA‐mutated hormone‐receptor positive metastatic breast cancer, tumor molecular profiling to identify somatic mutations and potential molecularly targeted agents is increasingly utilized in the treatment of advanced breast cancer.AimCombining germline and somatic sequencing (paired testing) offers an advantage over a single technique approach. Our study evaluates the role of paired testing on the management of breast cancer patients.Methods and ResultsForty‐three breast cancer patients treated at Rush University Medical Center underwent paired germline and somatic variant testing in 2015 to 2017. A retrospective chart review was conducted with the analysis of demographic, clinical, and genomic data. Three actionable germline variants were found in the CHEK2 (2) and ATM (1) genes. 95% of tumors had somatic mutations. Seventy‐seven percent of tumors had genomic alterations targetable with agents approved for breast cancer and 88% had molecular targets for agents approved for other cancers. Clinical examples of such use are described and potential future directions of tumor and paired testing are discussed.ConclusionsGermline variants were present in a relatively small patient group not routinely tested for inherited alterations. Potentially targetable somatic alterations were identified in the majority of breast cancers. Paired testing is a feasible and efficient approach that delivers valuable information for the care of breast cancer patients and eliminates serial testing.

Abstract 4624: Should genetic testing for cancer predisposition be standard-of-care for women with invasive breast cancer: The Murtha Cancer Center experience

Abstract Background: Currently, genetic testing is recommended to those patients diagnosed with breast cancer at a young age, with triple negative disease, Ashkenazi ancestry and/or a significant family history of breast, ovarian, prostate or pancreatic cancer. This precludes the opportunity to apply precision medicine approaches to women who do not meet these criteria. Timing and uptake of testing in high-risk patients and frequency of mutation detection in low-risk patients was evaluated in a cohort of women with invasive breast cancer treated at the Murtha Cancer Center of the Walter Reed National Military Medical Center (MCC/WRNMMC), the largest hospital of the Department of Defense health-care system. Methods: 1,231 women enrolled in the Clinical Breast Care Project of the MCC/WRNMMC 2001-2018 with invasive breast cancer. Genetic risk status was estimated using NCCN BRCA1/2 Testing Criteria. Panel testing was performed in the research laboratory for 1,043 women who had genomic (blood) DNA available. Genetic variants across 94 cancer predisposition genes were classified as pathogenic, variant of unknown significance (VUS) or benign using the ClinVar database. Results: Using NCCN version 1.2018 criteria, 57.8% of patients were eligible for genetic testing. Uptake of testing within the high-risk group was 40.0%; those who pursued genetic testing were significantly (p<0.001) younger and more likely to be college educated. Time-to-testing ranged from 0 to 15.3 years post-diagnosis and 6.3% of women pursued clinical testing only after a second tumor event. 19.3% of the high-risk women with clinical testing, 7.5% of high-risk women who did not pursue clinical testing and 4.4% of low-risk women carried a pathogenic or likely pathogenic mutation. Conclusions: More than 4% of breast cancer patients who chose not to pursue or were ineligible for genetic testing harbored pathogenic mutations in cancer predisposition genes. These data suggest that inclusion of panel testing at the time of diagnosis would allow for appropriate surveillance and treatment strategies to be employed to reduce the risk of secondary tumors and improve patient outcome. The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Seth Rummel, Leann Lovejoy, Clesson Turner, Craig Shriver, Rachel Ellsworth. Should genetic testing for cancer predisposition be standard-of-care for women with invasive breast cancer: The Murtha Cancer Center experience [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4624.

Abstract B056: Assessing knowledge of genetic testing for inherited cancer among registry-based young black breast cancer survivors and predominantly non-Hispanic white clinic-based patients

Abstract Introduction: Practice guidelines put forth through the American Society of Clinical Oncology (ASCO) evolved to encompass a new method of testing whereby multiple genes are tested in parallel (i.e., multi-gene panel testing) and racial disparities in genetic testing rates persist. To measure and compare knowledge of inherited cancer predisposition and multi-gene panel testing across racially diverse patient groups, we administered a newly developed and validated knowledge scale aligned with the 2016 ASCO guidelines. Methods: Online survey data inclusive of 14 knowledge questions was collected among Black women diagnosed with breast cancer at or below age 50 recruited through the Tennessee and Florida state cancer registries (“Registry group”; N=39) and an insured, predominately non-Hispanic White patient population referred for cancer genetic risk assessment at the Vanderbilt Hereditary Cancer Clinic (“Clinic group”; N= 55). Demographic and clinical information were compared using Chi-Square and Fisher’s Exact tests. Mean knowledge scores were calculated and compared using multiple regression analysis. Results: Rates of cancer among the Registry and Clinic groups were 100% and 49% (p<.0001), and rates of previous genetic testing were 69% and 13% (p<.0001). Mean knowledge scores were 6.10 and 6.75. When controlling for race, cancer history, and previous genetic testing, knowledge was not significantly different between the two groups (p=0.507). The lowest scoring knowledge questions among the Registry and Clinic groups included: 1) understanding of a variant of uncertain significance (15% and 11%); 2) knowledge of impact of genetic test results on supplemental insurance (21% and 11%); and 3) the types of possible test results (15% and 18%). Conclusion: These findings demonstrate similar knowledge of inherited cancer predisposition between a predominantly non-Hispanic White clinic-based population and a registry-based population of young Black breast cancer survivors; however, additional analyses should be performed as sample size increases. Knowledge about the possible results of genetic testing and the lack of protection against discrimination by supplemental insurers (e.g., life and disability insurance) was low across both groups; thus, should be a focus for improvement given that it could have real-world implications for decision-making. It remains important to assess knowledge of inherited cancer across diverse patient groups to develop effective strategies and interventions to increase knowledge across populations, including those with recognized disparities. Citation Format: Sydney Cadiz, Sonya Reid, Brenda Zuniga, Ann Tezak, Anne Weidner, Tuya Pal. Assessing knowledge of genetic testing for inherited cancer among registry-based young black breast cancer survivors and predominantly non-Hispanic white clinic-based patients [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B056.

Family cancer patterns and variation by race and ethnicity among individuals with pathogenic variants in multi-gene cancer predisposition panels at a large urban comprehensive cancer center.

e13540 Background: The identification of pathogenic variants and variants of unknown significance (VUS) in multi-gene cancer predisposition testing raises new questions regarding cancer risk and management. We evaluated the personal and family cancer patterns and variation by race and ethnicity, among individuals positive for pathogenic variants in non-BRCA1/ 2 cancer predisposing genes. Methods: The Karmanos Cancer Institute (KCI) Cancer Genetics database was queried from May 13, 2013 through December 31, 2018. There were 3,544 unrelated individuals evaluated for hereditary cancer predisposition of whom 1,868 had 18-gene panel testing at 6 sites across Michigan. Data was collected on personal and family cancer history including ages at diagnosis utilizing a 3-generation pedigree, self-identified race and ethnicity and results of genetic testing. We describe the prevalence of pathogenic variants by proband cancer diagnosis, family history, race, and ethnicity. Results: The race/ethnic distribution of the tested cohort included 67.5% non-Hispanic White (NHW), 24.4% African American (AA), 2.1% Arab, 1.8% Ashkenazi Jewish (AJ), 1.0% Hispanic, and 3.4% other. The distribution of cancer diagnoses included 40.6% breast, 5.5% ovarian, 4.1% colon, 3.5% endometrial, 2.0% pancreas and 39.7% unaffected. Pathogenic variants were seen in 151 (8.1%) individuals and VUS in 309 (16.5%). The five most common pathogenic variants were CHEK2 (40), MUTYH (22), ATM (20), and PALB2 (18). The most common pathogenic variants by race and ethnicity were CHEK2 (NHW), RAD51C (AA), PALB2 (Arab), CHEK2, MSH6 (AJ), and none in Hispanics. Variants associated with the four most common cancer types were breast ( CHEK2 ), ovarian ( CHEK2, MUTYH, BRIP1), colon ( ATM), and endometrial ( MSH6, PALB2). Of 40 individuals with CHEK2 variants, 92.5% were NHW, and 34 (85%), 31 (78%), 10 (25%), 1 (2.5%) had family history of breast cancer, breast cancer before age 50, ovarian, and colon cancer, respectively. Of 20 with ATM variants, 95% were NHW, 13 had family history data and 10 (76.9%), 8 (61.5%), 2 (15.4%), 1 (7.7%) had family history of breast, breast cancer before age 50, ovarian, and colon cancer, respectively. Conclusions: Pathogenic variants seen using multigene panel testing differ by race, ethnicity and personal/family history of cancer. This data will inform genetic counseling strategies in regards to cancer risk and management. Data on additional genes updated through 2019 will be presented.

Optimal age for genetic cancer predisposition testing in hereditary SMARCA4 Ovarian Cancer Families: How young is too young?

Small cell carcinoma of the ovary, hypercalcemic type is a rare, aggressive, and typically fatal ovarian cancer that primarily affects young women less than 40 years of age. It is caused by a pathogenic variant in the SMARCA4 gene, with nearly half of patients found to have germline pathogenic variants and the remainder demonstrating somatic SMARCA4 pathogenic variants. This case report discusses an illustrative case and explores the existing data and potential recommendations to optimize timing of genetic testing in family members, given the presence of a familial germline pathogenic variant.

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

How the "control-fate continuum" helps explain the genetic testing decision-making process: a grounded theory study.

Genetic testing decision-making for cancer predisposition is inherently complex. Understanding the mechanisms and influencing factors of the decision-making process is essential for genetic counselling and has not yet been investigated in Switzerland. This study's aim is thus to provide a theory about the individual's decision-making process regarding genetic testing for cancer predispositions in order to provide medical geneticists and genetic counsellors with insights into the needs and expectations of counsellees. We interviewed at-risk individuals who underwent genetic counselling in a clinical setting in Switzerland, using a grounded theory approach. Based on the interview data, we propose that a control-fate continuum, which is part of the individuals' life philosophy, importantly influences the decision-making process. Those in need for control decide differently compared with those leaving their future to fate. Several psychosocial factors influence the position on the control-fate continuum: "looking for certainty"; "anticipating consequences"; "being socially influenced"; "simplifying risks"; and "deciding intuitively vs reflectively". The control-fate continuum theory gives insights into the possible reasons behind decision-making regarding genetic testing for cancer predispositions. It includes both acceptors and decliners of genetic testing. Our theory helps healthcare professionals offering genetic counselling to anticipate problems within at-risk families and adapting their services to people's needs.

Abstract P6-08-19: Germline mutation prevalence among US and non-US Hispanic patients undergoing genetic testing for breast and ovarian cancer predisposition

Abstract Background: A variety of studies have examined the prevalence of germline mutations in patients undergoing genetic testing for a wide variety of breast cancer predisposition genes. Many of these studies have focused on patients of Northern European descent, leaving variant prevalence and clinical presentations of patients from underrepresented, and often underserved, populations much less well understood. Our study aimed to examine the prevalence of germline mutations among referred patients from Mexico, Central and South America, as well as a comparative population of Hispanic patients from the United States. Methods: We analyzed a de-identified laboratory-based cohort of patients who had received physician-ordered germline multigene panel test results between December 2014 and June 2019. Inclusion criteria for this study were a personal or family history of breast or ovarian cancer, and either (a) an ordering physician based in Mexico, Central America, or South America, or (b) a Hispanic self-reported ethnicity and a US based ordering physician. For this analysis, Mexican patients were combined with Central Americans. Panel size was per physician discretion, and most (>70%) physicians chose large (at least 20 gene) panels of high- and moderate-risk genes including BRCA1, BRCA2, PALB2, CHEK2, ATM, and TP53, among others. Full gene sequencing and deletion/duplication analysis were performed as described previously [PMID: 26207792] and variants were classified using a framework based on the ACMG/AMP guidelines for variant interpretation [PMID: 28492532]. Results: Of the 25,249 participants who met criteria, 18,513 were self-identified Hispanic-Amercians and 6,736 were non-US participants. Of the non-US group, 6,398 were from South America (including 1200 from Chile and 3781 from Brazil) while 273 were from Mexico and 65 from Central America. Pathogenic or Likely Pathogenic variants were uncovered in 14.4% of all participants, with 1864 findings (representing 7.4% of participants) in BRCA1 or BRCA2, and 1769 (7.0% of participants) in other cancer risk genes. Stratified by location, mutation positive rates were highest among Central (26.9%) and South Americans (19.2%), and lowest among the US Hispanics (12.5%). Based on NCCN guidelines, many of these findings would warrant consideration of a change in care for the patient and/or reflex testing of family members. Conclusions: Cancer patients in Mexico, Central, and South America may have less access to germline genetic testing than patients in (for example) the United States, although our study suggests that Latin American patients and their families can benefit from genetic testing at least at the same rate as Hispanic patients in the US. The higher positive rate among Central and South Americans in this study compared to Hispanic-Americans may be due to referral patterns and cost impact, although this question requires further study. The relative VUS rates between populations, mutation rates for specific clinical presentations, and relevant psychosocial issues also need further study to help maximize the utility of germline genetic testing in Latin America. Citation Format: Stephen E Lincoln, Daniel Pineda-Alvarez, Scott T Michalski, Shan Yang, Edward D Esplin. Germline mutation prevalence among US and non-US Hispanic patients undergoing genetic testing for breast and ovarian cancer predisposition [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-19.

A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients

PurposeDespite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include. MethodsTo inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT. ResultsWe identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria. ConclusionOpportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.

Should Genetic Testing for Cancer Predisposition Be Standard-of-Care for Women with Invasive Breast Cancer? The Murtha Cancer Center Experience.

Currently, genetic testing is offered only to women diagnosed with breast cancer who meet a defined set of criteria and is not included as standard-of-care treatment at the time of diagnosis. Thus, a significant number of women diagnosed with breast cancer may miss the opportunity for precision medical treatment and risk management. The effects of eligibility, timing, and uptake of genetic testing were evaluated in a cohort of women with invasive breast cancer diagnosed between 2001–2018. Risk status was estimated using NCCN BRCA1/2 testing criteria and panel testing was performed for all women who had genomic DNA available. Of the 1231 women, 57.8% were eligible for genetic testing. Uptake of testing within high-risk women was 42.7% of which 6.6% pursued clinical testing only after a second tumor event. Mutation frequencies were 15.8%, 5.5%, and 4.0% in high-risk women with clinical testing, high-risk women without clinical testing, and low-risk women, respectively. More than 4% of all patients harbored pathogenic or likely pathogenic mutations detected only in the research setting. Inclusion of panel testing at the time of diagnosis would allow for appropriate surveillance and treatment strategies to be employed to reduce the risk of secondary tumors and improve patient outcome.

Impact of free cancer predisposition cascade genetic testing on uptake in Singapore

Cascade testing for cancer predisposition offers a highly efficient and cost-effective method for identifying individuals at increased risk for cancer, in whom targeted interventions can often improve survival. The aim of this study was to determine the impact of free cascade testing on uptake and identify other associated factors. Demographic and clinical data were gathered prospectively for 183 probands found to have a pathogenic variant associated with cancer predisposition and their 826 first-degree relatives (FDRs). The provision of free cascade testing was significantly associated with uptake (21.6% vs 6.1%; χ2, P < 0.001). Relationship type between FDR and proband and FDR age also demonstrated significant associations, suggesting greater engagement amongst younger generations. Overall, 29.0% (53/183) of families had at least 1 FDR who underwent cascade testing. Of these families, 67.9% (36/53) had an uptake rate of at least 40.0%. Cost is a significant barrier to cascade testing uptake in Singapore. Tailored interventions targeting underrepresented groups and genetic counseling approaches supporting family communication and decision-making are necessary.

Risks of Solid Tumors in Heterozygous Carriers of Recessive Syndromes.

Expanded gene panel testing for hereditary cancer predispositions using massive parallel sequencing can identify heterozygous pathogenic variants of genes that cause autosomal recessive inherited cancer syndromes. There are no clinical guidelines regarding assessment of the risk of developing solid tumors or for developing appropriate surveillance strategies for heterozygotes for most of these genes, nor is there delineation with respect to the management for genetic testing of relatives and partners. Based on current knowledge, our aim was to create &#8220;Czech guidelines&#8221; for these cases. Here, we present an overview of the selected genes for autosomal recessive inherited tumor syndromes. The genes were divided into two groups: genes causing Fanconi anemia and genes causing other autosomal recessive inherited tumor syndromes. A summary table was created for each group. The table shows the population frequency of heterozygotes, the cancer risk for heterozygotes, the proposed surveillance strategy, and recommendations for family prediction and genetic testing of partners. Predictive testing should be performed in the case of heterozygotes that have an increased risk of cancer and/or as prerequisite to further reproduction of heterozygotes for a given gene with significant population frequency (this allows an estimation of the risk of autosomal recessive syndrome for children of heterozygote for mutation). These suggestions and recommendations are based on current knowledge and would need to be further corrected in the future based on increasing knowledge of existing or as-yet-unidentified genes. The authors thank to all the staff of the Molecular Genetic Laboratory of the GENNET Medical Genetics and Reproductive Medicine Center for their cooperation. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 3. 2019 Accepted: 2. 5. 2019.

Errors in Genetic Testing: The Fourth Case Series

In this ongoing national case series, we document 25 new genetic testing cases in which tests were recommended, ordered, interpreted, or used incorrectly. 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. 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. 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.

EMR documentation of genetics evaluations in patients with ovarian cancer.

e13156 Background: Genetic testing for hereditary cancer predisposition has become increasingly complex yet impactful. Provider knowledge of test results influences risk management, implications for family members, and therapeutics. Currently, it’s unknown if genetic test (GT) results are appropriately recorded and accessible within the electronic medical record (EMR). Methods: We conducted a single-institution retrospective chart review to examine clinical diagnoses, family history of cancer, genetics referrals, and genetics services received at University of Pennsylvania’s Cancer Risk Evaluation Program (CREP) or elsewhere. The study cohort included new and prevalent cases of ovarian cancer (OC) seen by either a gynecologic or medical oncologist at the University of Pennsylvania in 2016. Analyses were conducted using SAS 9.4. Results: 667 women (83% white, 9% black, 4% Asian; mean age 61) with OC were included. 58% had a documented family history of breast, ovarian, prostate or pancreas cancer. 48% had documentation of referral to genetic testing and an additional 26% had documentation of testing outside of CREP. 26% had no documentation of referral or testing. Of those referred to CREP, 75% had genetic testing: in total 62% of the cohort had documented testing. 94% of those tested had a result documented in a provider note, and 64% had a scanned testing report uploaded into the EMR, including 74.3% of those tested through CREP and 25.7% of those tested outside. Among the 118 pathogenic mutations, 70% were documented on the EMR “problem list.” Conclusions: In this study, most, though not all, OC patients had documentation of a GT referral or testing in the EMR. Although GT results were routinely included in progress notes, these reports were less commonly scanned into the EMR (particularly for those tested outside Penn) or included in the EMR “problem list” which is both searchable and immediately visible. Capturing genetic data in a uniform and easily accessible manner within the EMR is necessary to maximize clinical utility of this information and should be a focus for EMR module development.

Gaining insights into the DICER1 syndrome: An early report from the Italian DICER1 registry.

1519 Background: DICER1 is a key endoribonuclease in the microRNA pathway that modulates gene expression. Germline loss of function variants in DICER1, first found in pleuropulmonary blastoma, have been subsequently linked to a variety of cancerous (and non) conditions referred to as DICER1 syndrome. In 2018, the Italian Society of Human Genetics launched an initiative aimed at establishing a national registry of DICER1 germline sequence variants. Methods: Centers involved in genetic testing for cancer predisposition were asked to report any identified DICER1 germline variants and related clinical information. Five University and/or research institutes filled-in the electronic survey. Informed consent was obtained from patients or their legal guardians prior to DNA testing by NGS and/or Sanger sequencing. Results: Six DICER1 sequence variants were identified in 11 individuals. Three missense variants are secondary results of NGS panels for cancer predisposition and lack definitive categorization in online databases. Three previously unreported variants are predicted to be protein truncating and, hence, likely pathogenic. Of these, DICER1 c.4844delA p.(Lys1615Argfs*5) and c.4886C &gt; G p.(Ser1629*) result from ad hoc testing offered to probands based on a history of early onset follicular thyroid carcinoma and botryoid-type embryonal rhabdomyosarcoma of the cervix and of pleuropulmonary blastoma 2nd type, respectively. DICER1 c.4643T &gt; A p.(Leu1548*), instead, results from whole exome sequencing in two siblings with malignant melanoma who tested non informative for alterations in the CDKN2A and CDK4 melanoma predisposing genes. Further investigation unearthed thyroid disease in the family and identified two other young carrier individuals, one unaffected and one thyroidectomized due to multinodular goiter. A DICER1 somatic hot spot sequence variant was detected in goiter specimens. Conclusions: Via the newly established national registry we uncovered novel DICER1 germline sequence variants and uncommon genotype-phenotype associations. Our joint effort will help us to refine our knowledge of the rare DICER1 syndrome , to inform research studies, and to improve testing and clinical management strategies.

Population-based cancer predisposition testing as a component of newborn screening: A cost-effectiveness analysis.

10021 Background: The role of population-based newborn genetic testing to identify infants at high risk of childhood-onset cancers has not been studied, despite the availability of cancer surveillance guidelines for early detection in high-risk infants and children. Methods: We developed the Precision Medicine Prevention and Treatment (PreEMPT) Model to estimate the value of targeted population-based newborn genomic sequencing (tNBS) for a select panel of genes associated with early onset pediatric malignancy. Cohorts of US newborns were simulated under tNBS screening vs. usual care, from birth to death. Six pediatric cancer predisposition syndromes were included in the model with mutations in RET, RB1, TP53, DICER1, SUFU or SMARCB1 assigned at birth, using mutation prevalence and disease risks drawn from the published literature, as well as SEER, ClinVar and gnoMAD databases. Newborns with mutations underwent cancer surveillance based on established guidelines for each gene-related pediatric malignancy. Survival benefit was modeled as a reduction in proportion of advanced disease, cancer deaths, and treatment-related late mortality risks. Costs were based on published literature and national databases. Results: In a typical US birth cohort of 4 million newborns, we estimated 1280 cancer cases in the malignancies associated with this gene panel would be detected before age 20 under usual care, resulting in 451 cancer deaths and 490 living with radiation exposure risks. tNBS would prevent 8 cancers (in RET mutation carriers), avert 34 deaths through surveillance, result in 3190 life-years (LY) gained and a 13% relative reduction in proportion of adult survivors at risk for radiation-associated late mortality. Given a sequencing cost of $30 (e.g., $5/gene), the incremental cost-effectiveness ratio (ICER) for tNBS was $230,500 per LY saved; if no additional cost was incurred beyond standard newborn screening, the ICER decreased to $101,100/LY. Conclusions: Population-based genetic testing of newborns can reduce mortality associated with pediatric cancers and could potentially be cost-effective as sequencing costs decline. Further work will include modeling a broader panel of predisposition genes.