mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.

Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.

Hospital-based ovarian cancer patient traceback program results in minimal genetic testing uptake.

OBJECTIVE: To determine the feasibility of hospital-based genetic counseling and testing (GC/T) Traceback for Ovarian Cancer (OC) patients, as proposed by the Division of Cancer Prevention and the Division of Cancer Control and Population Sciences, National Cancer Institute. METHODS: Living patients with OC were sent a letter explaining the availability of guideline-supported GC/T for at least BRCA1/2 and surrogates of deceased patients were called on the telephone. Outcomes of contact attempts were systematically recorded and statistically described. RESULTS: 598 Traceback-eligible OC patients diagnosed from 2006 to 2016 were identified (163 presumed-living and 435 deceased). Two living patients called our office and scheduled an appointment for GC/T after receiving a letter. For surrogates of prior patients, successful contact occurred in 25% of call attempts. Fourteen individuals (2 living patients and 12 surrogates) underwent genetic counseling. Of those 14, 10 individuals consented to genetic testing and 5 followed through with sample collection. None of these individuals had pathogenic variants (PVs). When surrogate call notes were reviewed, 58% reflected positive responses to contact, however 42% were noted to have negative or indifferent responses, which were most common among spouses. Total time spent for hospital-based Traceback was 109 h. CONCLUSIONS: Overall, hospital-based Traceback via letter and telephone contact of surrogates is time-intensive and results in minimal uptake of GC/T. To practically execute this type of outreach program, health systems should consider collection of alternative contact information to allow for electronic communication of patient surrogates. Our study also underscores the importance of timely GC/T while patients are in active cancer care.

Concurrent germline BRCA1, BRCA2, and CHEK2 pathogenic variants in hereditary breast cancer: a case series.

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.

Operationalizing the Reciprocal Engagement Model of Genetic Counseling Practice: a Framework for the Scalable Delivery of Genomic Counseling and Testing.

With the advent of widespread genomic testing for diagnostic indications and disease risk assessment, there is increased need to optimize genetic counseling services to support the scalable delivery of precision medicine. Here, we describe how we operationalized the reciprocal engagement model of genetic counseling practice to develop a framework of counseling components and strategies for the delivery of genomic results. This framework was constructed based upon qualitative research with patients receiving genomic counseling following online receipt of potentially actionable complex disease and pharmacogenomics reports. Consultation with a transdisciplinary group of investigators, including practicing genetic counselors, was sought to ensure broad scope and applicability of these strategies for use with any large-scale genomic testing effort. We preserve the provision of pre-test education and informed consent as established in Mendelian/single-gene disease genetic counseling practice. Following receipt of genomic results, patients are afforded the opportunity to tailor the counseling agenda by selecting the specific test results they wish to discuss, specifying questions for discussion, and indicating their preference for counseling modality. The genetic counselor uses these patient preferences to set the genomic counseling session and to personalize result communication and risk reduction recommendations. Tailored visual aids and result summary reports divide areas of risk (genetic variant, family history, lifestyle) for each disease to facilitate discussion of multiple disease risks. Post-counseling, session summary reports are actively routed to both the patient and their physician team to encourage review and follow-up. Given the breadth of genomic information potentially resulting from genomic testing, this framework is put forth as a starting point to meet the need for scalable genetic counseling services in the delivery of precision medicine.

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure.

PURPOSE: This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure. METHODS: Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n = 65) or metoprolol (n = 33). RESULTS: CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02-0.75] p = 0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84-10.30] p = 0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day). CONCLUSION: Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

Outcomes of a Randomized Controlled Trial of Genomic Counseling for Patients Receiving Personalized and Actionable Complex Disease Reports.

There has been very limited study of patients with chronic disease receiving potentially actionable genomic based results or the utilization of genetic counselors in the online result delivery process. We conducted a randomized controlled trial on 199 patients with chronic disease each receiving eight personalized and actionable complex disease reports online. Primary study aims were to assess the impact of in-person genomic counseling on 1) causal attribution of disease risk, 2) personal awareness of disease risk, and 3) perceived risk of developing a particular disease. Of 98 intervention arm participants (mean age = 57.8; 39% female) randomized for in-person genomic counseling, 76 (78%) were seen. In contrast, control arm participants (n = 101; mean age = 58.5; 54% female) were initially not offered genomic counseling as part of the study protocol but were able to access in-person genomic counseling, if they requested it, 3-months post viewing of at least one test report and post-completion of the study-specific follow-up survey. A total of 64 intervention arm and 59 control arm participants completed follow-up survey measures. We found that participants receiving in-person genomic counseling had enhanced objective understanding of the genetic variant risk contribution for multiple complex diseases. Genomic counseling was associated with lowered participant causal beliefs in genetic influence across all eight diseases, compared to control participants. Our findings also illustrate that for the majority of diseases under study, intervention arm participants believed they knew their genetic risk status better than control arm subjects. Disease risk was modified for the majority during genomic counseling, due to the assessment of more comprehensive family history. In conclusion, for patients receiving personalized and actionable genomic results through a web portal, genomic counseling enhanced their objective understanding of the genetic variant risk contribution to multiple common diseases. These results support the development of additional genomic counseling interventions to ensure a high level of patient comprehension and improve patient-centered health outcomes.

Counselees' Perspectives of Genomic Counseling Following Online Receipt of Multiple Actionable Complex Disease and Pharmacogenomic Results: a Qualitative Research Study.

Genomic applications raise multiple challenges including the optimization of genomic counseling (GC) services as part of the results delivery process. More information on patients' motivations, preferences, and informational needs are essential to guide the development of new, more efficient practice delivery models that capitalize on the existing strengths of a limited genetic counseling workforce. Semi-structured telephone interviews were conducted with a subset of counselees from the Coriell Personalized Medicine Collaborative following online receipt of multiple personalized genomic test reports. Participants previously had either in-person GC (chronic disease cohort, n = 20; mean age 60 years) or telephone GC (community cohort, n = 31; mean age 46.8 years). Transcripts were analyzed using a Grounded Theory framework. Major themes that emerged from the interviews include 1) primary reasons for seeking GC were to clarify results, put results into perspective relative to other health-related concerns, and to receive personalized recommendations; 2) there is need for a more participant driven approach in terms of mode of GC communication (in-person, phone, video), and refining the counseling agenda pre-session; and 3) there was strong interest in the option of follow up GC. By clarifying counselees' expectations, views and desired outcomes, we have uncovered a need for a more participant-driven GC model when potentially actionable genomic results are received online.

Genetic Knowledge Among Participants in the Coriell Personalized Medicine Collaborative.

Genetic literacy is essential for the effective integration of genomic information into healthcare; yet few recent studies have been conducted to assess the current state of this knowledge base. Participants in the Coriell Personalized Medicine Collaborative (CPMC), a prospective study assessing the impact of personalized genetic risk reports for complex diseases and drug response on behavior and health outcomes, completed genetic knowledge questionnaires and other surveys through an online portal. To assess the association between genetic knowledge and genetic education background, multivariate linear regression was performed. 4 062 participants completed a genetic knowledge and genetic education background questionnaire. Most were older (mean age: 50), Caucasian (90 %), female (59 %), highly educated (69 % bachelor's or higher), with annual household income over $100 000 (49 %). Mean percent correct was 76 %. Controlling for demographics revealed that health care providers, participants previously exposed to genetics, and participants with 'better than most' self-rated knowledge were significantly more likely to have a higher knowledge score (p < 0.001). Overall, genetic knowledge was high with previous genetic education experience predictive of higher genetic knowledge score. Education is likely to improve genetic literacy, an important component to expanded use of genomics in personalized medicine.

Clinically relevant lessons from Family HealthLink: a cancer and coronary heart disease familial risk assessment tool.

PURPOSE: A descriptive retrospective study was performed using two separate user cohorts to determine the effectiveness of Family HealthLink as a clinical triage tool. METHODS: Cohort 1 consisted of 2,502 users who accessed the public website. Cohort 2 consisted of 194 new patients in a Comprehensive Breast Center setting. For patient users, we assessed documentation of family history and genetics referral. For all users seen in a genetics clinic, the Family HealthLink assessment was compared with that performed by genetic counselors and genetic testing outcomes. RESULTS: For general public users, the percentage meeting high-risk criteria were: for cancer only, 22.2%; for coronary heart disease only, 24.3%; and for both diseases, 10.4%. These risk stratification percentages were similar for the patient users. For the patient users, there often was documentation of family history of certain cancer types by oncology professionals, but age of onset and coronary heart disease family history were less complete. Of 142 with high-risk assignments seen in a genetics clinic, 130 (91.5%) of these assignments were corroborated. Forty-two underwent genetic testing and 17 (40.5%) had new molecular diagnoses established. CONCLUSION: A significant percentage of individuals are at high familial risk and may require more intensive screening and referral. Interactive family history triage tools can aid this process.Genet Med 17 6, 493-500.

Teaching genomic counseling: preparing the genetic counseling workforce for the genomic era.

Genetic counselors have a long-standing history of working on the clinical forefront of implementing new genetic technology. Genomic sequencing is no exception. The rapid advancement of genomic sequencing technologies, including but not limited to next generation sequencing approaches, across all subspecialties of genetic counseling mandates attention to genetic counselor training at both the graduate and continuing education levels. The current era provides a tremendous opportunity for counselors to become actively involved in making genomics more accessible, engaging the population in decisions to undergo sequencing and effectively translating genomic information to promote health and well-being. In this commentary, we explore reasons why genomic sequencing warrants particular consideration and put forward strategies for training program curricula and continuing education programs to meet this need.

Assessing the general public's view of direct-to-consumer (DTC) genetic testing and their interpretation of DTC website disclaimer messages.

The general public continues to show increased interest and uptake of Direct-to-Consumer (DTC) genetic testing. We conducted an online survey (N = 405) to assess genetics knowledge, interest, and outcome expectancy of DTC genetic testing before and after exposure to a sample DTC disclaimer message. Descriptive statistics were used to analyze the relationship between previous genetic knowledge, attitudes and self-reported systematic processing of a sample DTC disclaimer message, outcome expectancies, and interest to pursue DTC genetic testing. Increased genetic knowledge and more positive attitudes towards DTC genetic testing were associated with increased self-reported systematic processing of the DTC disclaimer message. Further, self-reported systematic processing of the DTC disclaimer message was associated with greater interest in pursuing DTC genetic testing but did not predict outcome expectancies. As DTC genetic testing continues to gain in popularity and usage, additional research is imperative to better understand participants' motivations and processing of the DTC disclaimer messages to improve the user experience.

Genetic counseling and testing for females at elevated risk for breast cancer: Protocol for the randomized controlled trial of the Know Your Risk intervention.

BACKGROUND: Genetic counseling and testing have an important role in the care of patients at elevated risk for breast cancer. However, conventional pre- and post-test genetic counseling is labor and time intensive, less accessible for patients living outside major urban centers, and impractical on a large scale. A patient-driven approach to genetic counseling and testing may increase access, improve patients' experiences, affect efficiency of clinical practice, and help meet workforce demand. The objective of this 2-arm randomized controlled trial is to determine the efficacy of Know Your Risk (KYR), a genetic counseling patient preference intervention. METHODS: Females (n = 1000) at elevated risk (>20% lifetime) for breast cancer will be randomized to the KYR intervention or conventional genetic counseling. The study will provide comprehensive assessment of breast cancer risk by multigene panel testing and validated polygenic risk score. Primary outcome is adherence to National Comprehensive Cancer Network guidelines for a clinical encounter every 6-12 months and an annual mammogram (breast MRI if recommended) determined by medical record review. Secondary outcomes include adherence to other recommended cancer screening tests determined by medical record review and changes in breast cancer knowledge, perception of risk, post-test/counseling distress, and satisfaction with counseling by completion of three surveys during the study. Study aims will be evaluated for non-inferiority of the KYR intervention compared to conventional genetic counseling. CONCLUSION: If efficacious, the KYR intervention has the potential to improve patients' experience and may change how genetic counseling is delivered, inform best practices, and reduce workforce burden. TRIAL REGISTRATION: ClinicalTrials.govNCT05325151.

Development of a web-based, theory-guided narrative intervention for women at elevated risk for breast cancer.

OBJECTIVE: To describe the development of a web-based, theory-guided narrative intervention that replaces conventional pre-test genetic counseling for women at elevated breast cancer risk. METHODS: We used an iterative process that was guided by health behavior theory and feedback from multiple stakeholder groups including: 1) content input from genetic experts; 2) study team input; 3) review of video storyboards, video example, study logo, recruitment materials, post-test patient preference counseling survey, and additional study surveys; 4) video series development; and 5) intervention review and finalization of study-related materials. RESULTS: The intervention is patient-centered providing convenience and an opportunity for an individual's preferences for post-test counseling delivery. The intervention's efficacy is being determined in a randomized controlled trial compared to conventional genetic counseling for adherence to recommended guidelines and changes in knowledge, perception of breast cancer risk, breast cancer-specific worry, and satisfaction with counseling. CONCLUSION: If efficacious, the intervention may improve the delivery of the genetic testing and counseling process, inform best practices, and reduce the genetic counseling workforce burden. PRACTICE IMPLICATIONS: The developed intervention has the potential to improve the genetic testing and counseling experience for women at elevated risk for breast cancer, inform best practices, and reduce genetic counseling workforce burden.

The risk of breast cancer in women with a BRCA1 mutation from North America and Poland.

Women with a BRCA1 mutation face a high lifetime risk of breast cancer. It is unknown to what extent environmental factors modify the inherent genetic risk. If women from different countries, but with similar mutations, experience different levels of cancer risk, nongenetic risk modifiers are likely to be present. Study subjects were a cohort of 1477 women with a BRCA1 mutation, from Canada (n = 358), the United States (n = 256) and Poland (n = 863). The women were followed for a mean of 4.3 years and 130 incident cases of breast cancer were recorded. Annual cancer incidence rates were calculated, and based on these, penetrance curves were constructed for women from North America and Poland. In a Cox proportional hazards model, residence in Poland, versus North America, was associated with an adjusted hazard ratio of 0.54 (95% CI 0.34-0.86; p = 0.01). The risk of breast cancer to age 70 was estimated to be 49% for women from Poland and 72% for women from North America. Among women with BRCA1 mutations, the risk of breast cancer in women who reside in Poland is less than that of women who reside in North America. The reasons for the difference are unknown, but this observation suggests that environmental factors or genetic modifiers are important in determining risk.

Cancer risks for relatives of patients with serrated polyposis.

OBJECTIVES: Serrated polyposis (hyperplastic polyposis) is characterized by multiple polyps with serrated architecture in the colorectum. Although patients with serrated polyposis are known to be at increased risk of colorectal cancer (CRC) and possibly extracolonic cancers, cancer risk for their relatives has not been widely explored. The aim of this study was to estimate the risks of CRC and extracolonic cancers for relatives of patients with serrated polyposis. METHODS: A cohort of the 1,639 first- and second-degree relatives of 100 index patients with serrated polyposis recruited regardless of a family history of polyps or cancer from genetic clinics in Australia, New Zealand, Canada, and the USA, were retrospectively analyzed to estimate the country-, age-, and sex-specific standardized incidence ratios (SIRs) for relatives compared with the general population. RESULTS: A total of 102 CRCs were observed in first- and second-relatives (SIR 2.25, 95% confidence interval (CI) 1.75-2.93; P<0.001), with 54 in first-degree relatives (SIR 5.16, 95% CI 3.70-7.30; P<0.001) and 48 in second-degree relatives (SIR 1.38, 95% CI 1.01-1.91; P=0.04). Six pancreatic cancers were observed in first-degree relatives (SIR 3.64, 95% CI 1.70-9.21; P=0.003). There was no statistical evidence of increased risk for cancer of the stomach, brain, breast, or prostate. CONCLUSIONS: Our finding that relatives of serrated polyposis patients are at significantly increased risk of colorectal and pancreatic cancer adds to the accumulating evidence that serrated polyposis has an inherited component.

Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients.

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.

Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations in CTNNB1 or APC: A Multi-institutional Retrospective Study.

PURPOSE: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments. EXPERIMENTAL DESIGN: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), and overall survival (OS). Kaplan-Meier analysis and Cox proportional hazards regression were performed to identify differences in cPFS, rPFS, TTNT, and OS by mutation subtype, desmoid tumor location, and treatment regimen. RESULTS: A total of 259 evaluable patients were analyzed for at least one of the survival outcomes, with 177 patients having mutation data. First- and second-line cPFS, rPFS, and TTNT were not significantly affected by mutation subtype; however, APC-mutant desmoid tumors demonstrated nonstatistically significant inferior outcomes. Extremity/trunk desmoid tumor location and treatment with doxorubicin-based, methotrexate/vinca alkaloids and sorafenib regimens were associated with better clinical outcomes compared with surgery or "other" therapies, including estrogen-receptor blockade and imatinib. OS was significantly worse with APC or CTNNB1 negative/other mutations. CONCLUSIONS: Mutation subtype did not affect responses to specific systemic therapies. APC mutations and nonextremity desmoid tumor locations remain prognostic for worse outcomes, and earlier initiation of systemic therapy for these higher-risk desmoid tumors should be prospectively evaluated. See related commentary by Greene and Van Tine, p. 3911.

MRI Volumetrics and Image Texture Analysis in Assessing Systemic Treatment Response in Extra-Abdominal Desmoid Fibromatosis.

Purpose To determine whether MRI volumetric and image texture analysis correlates with treatment-induced biologic changes in desmoid fibromatosis (DF) earlier than conventional response criteria. Materials and Methods This retrospective study included 27 patients with histologically proven extra-abdominal DF who were managed with active surveillance or systemic therapy (from 2004 to 2016). MRI volumetric and image texture parameters were derived from manual tumor segmentations, and tumor signal intensity was normalized to muscle. Results were compared with objective response rates based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, World Health Organization (WHO) lesion response, volumetrics, and MRI-modified Choi criteria. Correlation coefficients (r) between image texture features and maximum tumor diameters were obtained by using a meta-analysis approach. Results The 27 included patients (mean age, 39 years; 74% women) were followed for an average of 4 years, comprising 207 distinct time-point assessments. The mean baseline tumor maximum diameter was 7.9 cm (range, 3.4-15.2 cm). Partial response (PR) rates as best response were 37%, 44%, 70%, and 81% by RECIST, WHO, volumetrics, and MRI-modified Choi criteria, respectively. Among the 10 tumors showing RECIST PR, a preceding MRI-modified Choi PR was observed in 70% (seven of 10), on average 1.3 years earlier. Multiple image texture parameters showed associations with objective measurements of tumor diameter including mean tumor-to-muscle signal ratio (r = 0.51; P = .004), median tumor-to-muscle signal ratio (r = 0.52; P = .003), energy (r = 0.48; P < .001), run entropy (r = 0.32, P = .04), and gray-level nonuniformity (r = 0.54; P ≤ .001). Conclusion Volumetric signal and image texture assessment allows more comprehensive analysis of DF biologic change and may permit early prediction of DF behavior and therapeutic response. Keywords: MR Imaging, Soft Tissues/Skin, Neoplasms-Primary © RSNA, 2021.

Characterization of BRCA1 ring finger variants of uncertain significance.

The majority of pathogenic mutations in BRCA1 result in a truncated protein. Although most missense changes in BRCA1 are of unknown functional significance, a handful of deleterious missense mutations have been identified. The majority of these occur in splice sites or highly conserved protein domains. Previously, we developed a predictive model, VUS Predict, to classify BRCA variants of uncertain significance as neutral or deleterious. It uses evolutionary prediction algorithms together with clinical information from cancer pathology reports and BRCA genetic testing results. Because of the higher probability that missense changes occurring in conserved BRCA1 domains are of pathogenic significance, we identified all individuals in our cohort who had been tested for BRCA1 and BRCA2 mutations who had missense changes in the BRCA1 ring finger domain and sought to classify those changes. We applied VUS Predict to three previously uncharacterized variants and four missense changes known to be deleterious. Two variants, L22S and T37K, were predicted to be deleterious and one variant, K45Q, was predicted to be neutral by VUS Predict. The mutations C39R, C44Y, C44S, and C61G were confirmed as deleterious.