Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation.

The complexities of gene expression pose challenges for the clinical interpretation of splicing variants. To better understand splicing variants and their contribution to hereditary disease, we evaluated their prevalence, clinical classifications, and associations with diseases, inheritance, and functional characteristics in a 689,321-person clinical cohort and two large public datasets. In the clinical cohort, splicing variants represented 13% of all variants classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUSs). Most splicing variants were outside essential splice sites and were classified as VUSs. Among all individuals tested, 5.4% had a splicing VUS. If RNA analysis were to contribute supporting evidence to variant interpretation, we estimated that splicing VUSs would be reclassified in 1.7% of individuals in our cohort. This would result in a clinically significant result (i.e., P/LP) in 0.1% of individuals overall because most reclassifications would change VUSs to likely benign. In ClinVar, splicing VUSs were 4.8% of reported variants and could benefit from RNA analysis. In the Genome Aggregation Database (gnomAD), splicing variants comprised 9.4% of variants in protein-coding genes; most were rare, precluding unambiguous classification as benign. Splicing variants were depleted in genes associated with dominant inheritance and haploinsufficiency, although some genes had rare variants at essential splice sites or had common splicing variants that were most likely compatible with normal gene function. Overall, we describe the contribution of splicing variants to hereditary disease, the potential utility of RNA analysis for reclassifying splicing VUSs, and how natural variation may confound clinical interpretation of splicing variants.

40 years and beyond for the National Society of Genetic Counselors: Reflections on genetic counseling practice.

The National Society of Genetic Counselors (NSGC) was established in 1979 and has grown from a small dedicated group of genetic counselors to over 5,000 certified genetic counselors in 2019. During this time period, there have been tremendous advances in the practice of genetic counseling, the availability of genetic testing, and the use of technology. These advances have significantly changed our roles and responsibilities and have contributed to the expansion and diversification of our field in clinical and non-clinical work settings. The launch of genetic counseling services in prenatal, pediatric, and adult genetics clinics has expanded to many medical specialties. Genetic counselors are also working in industry, public health, policy, education, research, and other work settings. With growth into new areas and the significant increase in the number of practitioners, genetic counselors have established themselves professionally and created opportunities where they can not only contribute to the delivery of quality genetic services, but lead the way. The counseling skills that are a core part of training as genetic counselors will continue to have broad application in diverse work settings and roles. Looking to the future, genetic counselors need to proactively consider tasks that artificial intelligence and other technologies can accomplish so that genetic counselors have the bandwidth to use their expertise to successfully and efficiently meet the growing demands for genetic counseling services. During the 40th anniversary celebration at the 2019 NSGC Annual Conference, three of NSGC's past presidents reflected on the early years of NSGC and clinical practice, recognized key accomplishments and where the profession stands today, and shared thoughts about the future of genetic counseling. Videos of the actual talks can be accessed by internet search 'NSGC Celebrates 40 Years' (https://www.nsgc.org/p/bl/et/blogid=53&blogaid=1162). A timeline of the genetic counseling profession is available at https://www.nsgc.org/page/nsgc-timeline.

Informing Women and Their Physicians about Recommendations for Adjunct Breast MRI Screening: A Cohort Study.

It is unclear how best to communicate recommendations for breast cancer screening with MRI as an adjunct to mammography for women at high risk. This study compares the rates of breast MRI screening for two different methods of communication. The retrospective IRB-approved cohort study was conducted at Invision Sally Jobe Breast Centers (ISJBC). ISJBC provided Gail model risk assessment to all women presenting for screening mammography. Women with scores ≥ 19.6% were considered to be high risk. Over 2 years, ISJBC used two different methods to inform women at elevated lifetime risk and their physicians about recommendations for adjunct MRI screening (N = 561, mean age = 52 years, s.d. = 8.7). During Window A, information was sent to referring physicians as a part of the dictated imaging report, while later, in Window B, the information was sent to referring physicians as well as to the women themselves in a letter. Analyses were stratified by mammography screening frequency. One-time screeners presented in only Window A or Window B. Repeat screeners came both in Window A and in Window B. Breast MRI screening rates were significantly higher in Window B than in Window A (one-time screeners, N = 459, 9.8% vs. 14.4%, p = 0.047; repeat screeners, N = 102, 0% vs. 6.9%, p = 0.016). Although an observational study cannot assess causality, direct communication of risk-based recommendations for adjunct breast MRI screening to women and to their referring physicians was associated with an increased rate of screening breast MRI completion at the same clinic at which the women underwent mammography.

Breast Cancer Risk Assessment Models and High-Risk Screening.

It is important to recognize that patients at high risk for breast cancer may benefit by following breast cancer screening paradigms that are more robust than those recommended for the average-risk population. Assessing individual cancer risk and using guidelines to determine if a patient is a candidate for genetic counseling and possibly genetic testing are essential components to comprehensive breast cancer screening.

Breast cancer risk assessment in 64,659 women at a single high-volume mammography clinic.

RATIONALE AND OBJECTIVES: In 2007, the American Cancer Society (ACS) recommended that women at elevated risk of breast cancer be screened with breast magnetic resonance imaging (MRI) as an adjunct to mammography. This study estimates the proportion of women presenting for screening mammography who are at elevated lifetime risk of breast cancer as determined by the Gail model. This study provides preliminary information for a proposed follow-up study, including the proportion of women who completed the recommended MRI at the same clinic that had conducted the risk assessment. MATERIALS AND METHODS: This study is an observational prospective cohort of 64,659 women presenting for mammographic screening at a single high-volume clinic. If a woman reported a first-degree maternal relative with breast cancer and had at least 20% lifetime risk on the Gail model, the radiologist's report included a recommendation that the primary care physician refer the woman for breast MRI screening. Records were examined to determine if women completed the recommended MRI at the clinic within one year of the initial risk assessment. RESULTS: Of 64,659 women, 1,246 (1.9%) had a lifetime risk of breast cancer of 20% or greater, and 436 (0.7 %) had a lifetime risk of breast cancer 25% or greater. Of the women at elevated risk, 173 (13.9%) completed the recommended breast MRI screening at the clinic within a year. CONCLUSION: The effectiveness of matching screening intensity to risk on cancer detection, biopsy rate, and cost should be evaluated by studying multiple clinics and multiple risk assessment tools.

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

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

Hereditary colorectal cancer in the gastroenterology clinic: how common are at-risk patients and how do we find them?

Colorectal cancer is the second leading cause of cancer deaths in the United States in both men and women and is thus a major public health problem. The American Cancer Society estimated that in 2007, approximately 153,760 people in the United States were diagnosed with colorectal cancer and about 52,180 died of the disease. Colorectal cancer is largely preventable, however, and often curable when detected early. About 80% of people with colorectal cancer seem to have sporadic disease with no evidence of inheriting the disorder, and the remaining 20% have a familial or hereditary risk. Identifying those with heritable cancers is best accomplished through a detailed family history, easily obtained by a trained nurse. With a detailed family history, risk can be assessed and further screening via colonoscopy or genetic testing may be undertaken. Unfortunately, to date, there is no universally accepted method to collect family health histories to determine the risk of hereditary colorectal cancer. This study field tested two different intake tools that collect personal and family history information for (1) evaluating their effectiveness in identifying patients at risk for hereditary colorectal cancer in a gastroenterology center; (2) determining patient, nurse, and physician satisfaction with each tool; and (3) assessing the prevalence of patients at risk for hereditary colorectal cancer in a gastroenterology center. A purposive sample of six gastroenterology practices across the United States was utilized. Eligible subjects included all patients seen in those practices over a 2-month time frame. Each intake tool was administered over a 4-week time frame. Satisfaction questionnaires were given to a random selection of subjects, as well as involved nurses and providers at each site. Overall prevalence of those at risk for hereditary colorectal cancer was 26% for all sites, ranging from 11%-39% across sites and tools. This study is significant because it revealed a fairly high percentage of people at risk for hereditary colorectal cancer and showed how an initial risk assessment can be easily done by professional nurses and other healthcare providers who are in a unique position to help reduce the incidence and mortality from colorectal cancer.