BACKGROUND:NCCN publishes genetic testing criteria based on personal and family cancer history (PFHx). Digital risk stratification tools may aid clinicians in the challenging task of systematically collecting this history and accurately identifying individuals who meet the criteria. A HIPAA-compliant digital tool (The Ambry CARE Program) integrates NCCN Guidelines and identifies patients who meet the NCCN criteria for hereditary breast, ovarian, pancreatic, and prostate cancer (HBOP), as well as Lynch syndrome and familial adenomatous polyposis (both related to hereditary colorectal cancer [CRC]). The purpose of this study was to validate the analytic accuracy of the tool's interpretation of the NCCN Guidelines compared with a certified genetic counselor (CGC). METHODS:This study, conducted by a diagnostic laboratory, included 2 phases: (1) development and internal verification of the tool using 1,300 theoretical clinical scenarios (913 HBOP and 394 CRC scenarios), with testing eligibility determined by internal CGC consensus and the tool; and (2) external analytical validation comparing CARE's interpretation of 400 deidentified real-world cases against CGC interpretation. Of the 400 cases, 200 met and 200 did not meet the criteria. Of the cases that met the criteria, based on CARE's interpretation, 150 met the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 2.2022), and 50 met the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal (Version 1.2021). RESULTS:There were no discrepancies in the internal verification when comparing the final consensus outcomes with the CARE outputs. In external validation, CARE accurately assessed 398 (99.5%) cases. In 17 cases, CARE made correct risk assessments, whereas CGCs did not. CONCLUSIONS:CARE accurately identifies individuals who meet NCCN testing criteria to aid in risk stratification. Digital tools such as this may be helpful in clinical practice for collecting PFHx and identifying candidates for genetic testing of hereditary cancers.

Background Developing an effective approach to the identification of individuals at increased cancer risk is key to preventing and/or providing early diagnosis of cancer. However, outside of targeted genetics clinics, under identification of individuals with hereditary cancer risk is well recognized, due in part to ever evolving complexity of germline genetic testing criteria and lack of systematic framework to perform robust risk assessment on all patients. In contrast, breast and imaging centers are ideally positioned to maximize the impact of positive genetic test results due to immediate availability of surveillance and diagnostic tools. Here we present data from breast and imaging centers using a patient-facing digital platform offered universally to all patients before their scheduled appointment designed to collect personal and family health information and assess cancer risk and genetic testing eligibility based on current guidelines. Methods We conducted a retrospective observational study of patients in breast and imaging centers who used a web-based risk stratification tool before standard ambulatory appointments to assess their lifetime risk for breast cancer based on the Tyrer-Cuzick (version 8.0) risk algorithm and eligibility for National Comprehensive Cancer Network (NCCN®) genetic testing criteria at the time of assessment. Testing criteria included hereditary breast, ovarian, pancreatic, and prostate cancers, Lynch syndrome, and familial adenomatous polyposis (FAP). Data was pulled for patients seen from June 2020 through May 2022 at participating breast and imaging centers throughout the United States. Outcome measures included percentage of individuals who completed the risk-assessment, met testing criteria, pursued germline genetic testing, received a positive germline result, and/or had a Tyrer-Cuzick breast cancer risk ≥20%. Results A total of 251,492 individuals completed assessments; 250,011 (99%) were females aged 18 years or older. Overall, at the time of assessment 80,814/251,492 (32.1%) met genetic testing criteria and 24.4% (19,694) of those meeting criteria opted to proceed with germline genetic testing. An additional 1,561 individuals who did not meet criteria pursued genetic testing. Of the 18,532 completed genetic tests, 1,507 (8.1%) had positive genetic test results. The majority of positive individuals (93%) met testing criteria. 40.7% (613/1,507) of positive results had an impact on breast cancer risk management options. In addition to individuals identified as high-risk through germline genetic testing evaluations, 13.1% (28,108/214,269) of individuals assessed using the Tyrer-Cuzick algorithm had ≥20% lifetime risk of breast cancer and met the threshold for modified medical management. Conclusion In this study, the web-based assessment tool provided a standardized workflow that enabled individuals interested in receiving cancer risk assessment and germline testing an opportunity to do so. When offered to all patients, this digital platform can offer a scalable opportunity for breast and imaging centers to identify individuals eligible for modified medical management for breast cancer risk and other inherited cancer syndromes, which may ultimately improve the prevention and early treatment of individuals with cancer predisposition. Citation Format: Heather Fecteau, Haley Keller, Carrie Horton, Carrie Milliard, Robert Pilarski, Lukas Lyon, Lily Hoang, Shannon Kieran. Expanding the reach of germline genetic testing: Use of web-based risk assessment to inform medical management amongst patients at breast and imaging centers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-13.

Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients' family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.

DNA germline genetic testing can identify individuals with cancer susceptibility. However, DNA sequencing alone is limited in its detection and classification of mRNA splicing variants, particularly those located far from coding sequences. Here we address the limitations of splicing variant identification and interpretation by pairing DNA and RNA sequencing and describe the mutational and splicing landscape in a clinical cohort of 43,524 individuals undergoing genetic testing for hereditary cancer predisposition.

Background: The National Comprehensive Cancer Network guideline on Genetic/Familial High Risk: Breast, Ovarian and Pancreatic Cancer (NCCN) recommends offering increased screening and risk-reduction options to women with a pathogenic/likely pathogenic variant (PV/LPV) in 8 clinically-actionable hereditary breast and ovarian cancer (HBOC) genes: ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, and TP53. These options range from biannual clinical breast exams and annual breast MRI screening to risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO). Yet health insurance company policies addressing the medical necessity of genetic testing for these genes vary widely. While some payers have adopted the NCCN testing criteria verbatim, others have made specific changes or have developed their own criteria. We sought to quantify the potential impact of this variability on access to enhanced medical management for carriers of PV/LPV in these 8 HBOC genes in a large cohort of patients undergoing genetic testing at a single commercial laboratory. Methods: We reviewed clinical and family histories for patients undergoing multigene panel testing that included testing for the 8 genes of interest and identified 107,344 patients who met NCCN testing criteria (excluding prostate cancer criteria, which were not assessed in this study) for HBOC (v.2.2021). We then compared the histories of these patients to testing criteria for 3 different payer groups: Aetna, Blue Shield of California/Federal Blue Cross-Blue Shield, and eviCore (used by over 30 payers including AmeriHealth, Highmark and Horizon). These are the largest payer groups in our cohort and together represent 19% of patients tested. For each patient we determined whether they met testing criteria for the 3 payer groups. For individuals found to have a PV/LPV we determined the potential missed management opportunities for those who would not have been tested under each payer’s criteria. In addition, we sought to estimate the maximal impact of this missed management for patients with BRCA PV/LPV (not accounting for patient age or medical history). Results: Among patients meeting NCCN testing criteria for HBOC, 10,10,477 (9.8%) were found to have PVs/LPVs in one of the 8 genes. Under the three payer policies 2% to 10.3% of all patients, and up to 4.0% (n=423) of PV/LPV carriers, would not have been eligible for genetic testing. Based on NCCN management guidelines, up to 423 eligible patients would not have been offered annual breast MRI, 208 patients would not have been offered RRM, and 163 eligible patients would not have been offered RRSO. This lack of testing access due to misaligned medical policies also represents missed opportunities for offering potentially life-saving screening and risk reduction measures to these patients as well. Assuming lifetime cancer risks of 85% for breast cancer and 40% for ovarian cancer, and risk-reduction of 95% with RRM and 80% with RRSO. Had all policies matched NCCN testing criteria, up to 132 breast cancers could have potentially been detected earlier or prevented and 52 ovarian cancers could potentially have been prevented in our cohort. Conclusions: In addition to complicating clinical practice, varying testing guidelines have broader implications. Our data show that a significant number of mutation carriers are being missed by payer policies that deviate from NCCN testing criteria. In turn, this represents missed opportunities to offer proactive screening and risk-reduction options that could potentially save lives for those at risk for hereditary cancer. Based on findings from other studies, these actions would likely reduce health insurer costs as well. Citation Format: Robert T Pilarski, Stephanie Noble, Lily Hoang, Randy Hew, Stephanie Gandomi, Holly LaDuca, Jill Dolinsky. Inequitable access to genetic testing leads to missed screening and prevention opportunities for individuals at risk for hereditary breast and ovarian cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-19.

Disparities in genetic test results for hereditary cancer predisposition are well known, whereby a higher rate of variants of uncertain significance (VUS) and a lower rate of pathogenic variants (PV) are identified in racial and ethnic minorities compared to non-Hispanic white (NHW) individuals. Lack of representation of non-white and Hispanic individuals in testing cohorts, published literature and population databases contributes to this disparity, as it limits the availability of evidence used towards variant classification (i.e., case-control data, proband counting co-segregation, population frequency).

Historically, genetic testing (and billing) for hereditary cancer risk was essentially performed gene by gene, with clinicians ordering testing only for the genes most likely to explain a patient's or family's cancer presentation, with laboratories typically charging $1,000 to $1,500 for each gene that was sequenced. Given the expense, only patients at high risk of having a hereditary syndrome were offered testing. With the introduction of next-generation sequencing technologies, however, laboratories are able to test for multiple genes at the same time with greater efficiency, significantly decreased costs, and relatively little increased expense when adding additional genes. This has drastically altered clinical practice so that clinicians now typically order testing for a panel of multiple genes for most patients. Although this approach has streamlined the diagnostic odyssey, it has introduced several problems, as well, including difficulties in choosing the appropriate panel test for a given patient, assessing the significance of identified genetic variants (including variants of uncertain significance [VUS]), and understanding the disease risks and management associated with pathogenic variants in a given gene. Many laboratories offer testing for genes that have limited data supporting their associated cancer risks, which then leads to an inability to set management guidelines based on that gene. In addition, testing larger numbers of genes increases the likelihood of finding one or more VUS, which introduce their own management issues. Thus, although panel testing has certainly moved clinical practice forward in many ways, it has also raised its own set of problems that increase the complexity of genetic counseling and highlight the need for education of community practitioners on the complexities and nuances of this testing. Whenever possible, testing should be performed by, or in consultation with, cancer genetics professionals.

Background Concurrent germline (g) pathogenic variants related to hereditary breast cancer represent a rare occurrence. While double heterozygosity in gBRCA1 and gBRCA2 has been reported in the past, herein we describe the first case of three known concurrent pathogenic variants identified in a family with a strong history of breast cancer. Case presentation The proband is a 55-year-old female diagnosed with synchronous bilateral breast cancers. She underwent a multi-gene panel testing indicating the presence of 3 concurrent heterozygous germline deleterious variants in BRCA1 (c.181T > G), BRCA2 (c.4398_4402delACATT), and CHEK2 (1100delC). The patient's two daughters (34 and 29 years-old) were found to be transheterozygous for inherited pathogenic variants in BRCA1 (c.181T > G) and CHEK2 (1100delC) genes. Conclusion The cancer risk and phenotypic manifestations associated with transheterozygous or multiple concurrent deleterious germline variants in hereditary breast cancer requires further investigation. A personalized approach to counseling, screening, and risk reduction should be undertaken for these individuals.

Hereditary endocrine tumor syndromes are rare conditions with overlapping features. It is imperative that healthcare providers differentiate between these syndromes for proper patient care. Advances in genetic testing technologies have increased utilization of genetic counseling and testing in this field; however, few endocrine cancer genetics clinics exist. Two years ago, a genetic counselor (GC) specializing in endocrine cancer genetics was added to the multidisciplinary team of the James Neuroendocrine/Thyroid Clinic at The Ohio State University. Here, we report on this experience. In total, 358 patients were seen. The majority were referred by medical oncology (n = 204; 57%) for a personal history of disease (n = 249; 81%). The most common referral indications were pancreatic neuroendocrine tumors (n = 44; 17%), multiple primary tumors (n = 37; 14%), and pheochromocytoma/paraganglioma (n = 35; 14%). Most patients completed genetic testing after genetic counseling (n = 200; 65%). Targeted gene panel testing was the most common testing ordered (n = 98; 32%). Thirty-one patients (15.5%) had ≥ one likely pathogenic variant (LPV) or pathogenic variant (PV) identified. Approximately 37% (n = 11) did not meet genetic testing guidelines for the gene they tested positive for. The most common genes with LPV/PVs were the SDH genes (n = 8) and MEN1 (n = 7). Referral indications with the highest likelihood of LPV/PVs were paraganglioma, medullary thyroid carcinoma, and multiple primary tumors. We believe this data can provide valuable guidance to healthcare providers who see patients with endocrine neoplasia or who are seeking to establish hereditary endocrine cancer clinics.

Introduction: Pharmacogenetic (PGx) testing can be useful for providing information about a patient’s drug response by increasing drug efficacy and decreasing the incidence of adverse drug events. While PGx tests were previously only offered to patients under healthcare provider supervision, they are now available as direct to consumer (DTC) tests. This study aimed to assess how accurately individuals from the general population were able to interpret a sample PGx test report and if accuracy differed based on individuals’ numeracy or prior genetic counseling (GC). Methods: We surveyed 293 individuals from the general population, ascertained through ResearchMatch. The survey included questions about PGx test interpretation, numeracy, and genetic literacy. Results: In our cohort, numeracy level impacted PGx result interpretation, with those of high numeracy performing statistically significantly better on both the table format and graphical format (p value = 0.002 and p value <0.001, respectively) and genetic knowledge questions (p value <0.001) than those with low/average numeracy. In addition, previous GC did not impact test interpretation or genetic knowledge, but the number of individuals with prior GC was small (n = 26). Discussion/Conclusion: We found that numeracy had a significant impact on correct interpretation of PGx test reports. Because many individuals in the USA have low numeracy levels, it is extremely important that patients do not make their own medication management decision based on the test results and that they consult with their physicians about their PGx testing. The importance of consultation and discussion with providers about results should be emphasized on the test report.

Recent evidence suggests that PALB2 variants may increase risk for the development of uveal melanoma and uveal melanocytic neoplasms. Here we report a case of an atypical choroidal nevus in a patient with a personal history of cancer and pathogenic PALB2 germline variant. A 75-year-old white female presented with an elevated predominantly amelanotic choroidal lesion OS. On examination and ophthalmic imaging, the mass measured 8.8 mm × 6.5 mm × 1.5 mm. The mass showed predominantly medium to high reflectivity on diagnostic A-scan and acoustic hollowing on B-scan. OCT over the lesion showed no subretinal fluid. The patient has a personal history of breast cancer and gastric adenoma and a strong family history of cancer. The patient was found to have a pathogenic truncating variant in PALB2 (rs118203998 c.3549C > A, p.Y1183*). Together with our previous findings of pathogenic PALB2 variants in uveal melanoma patients, this new finding of an atypical choroidal nevus in a patient with a pathogenic PALB2 germline variant suggests that pathogenic PALB2 variants may be a risk factor for uveal melanocytic neoplasms. This finding warrants further assessment of the prevalence and progression of uveal melanocytic neoplasms in PALB2 pathogenic variant carriers.

Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.

With the introduction of panel and direct-to-consumer testing, genetic testing has become commonplace in recent years, paving the way for both increased awareness around prevalent genetic cancer risks, and also an onslaught of misinformation. At the NCCN 2020 Virtual Annual Conference, Dr. Tuya Pal led a panel of experts in discussing the utility and difficulties associated with multigene testing, the emerging role of moderate-penetrance genes in defining risks for hereditary cancer, and the controversies associated with direct-to-consumer genetic testing services.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.