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Purpose: Some variants identified by multigene panel testing of DNA from blood present with low variant allele fraction (VAF), often a manifestation of clonal hematopoiesis. Research has shown that the proportion of variants with low VAF is especially high in TP53, the Li-Fraumeni syndrome gene. Based on the hypothesis that variants with low VAF are positively selected as drivers of clonal hematopoiesis, we investigated the use of VAF as a predictor of TP53 germline variant pathogenicity., Methods: We used data from 260,681 TP53 variants identified at 2 laboratories to compare the distribution of pathogenic and benign variants at different VAF intervals., Results: Likelihood ratios toward pathogenicity associated with a VAF < 26% equated to the American College of Medical Genetics/Association of Molecular Pathology strong strength level and were applicable for 1 in 5 variants of unknown significance., Conclusion: In conclusion, detection of variants with low VAF in blood can be considered an in vivo functional assay to aid assessment of TP53 variant pathogenicity., Competing Interests: Conflict of Interest Tina Pesaran, Kelly McGoldrick, Jill Dolinsky, and Lily Hoang are paid employees of Ambry Genetics. All other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers., Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort., Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10 -72 ). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10 -50 ). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10 -22 ) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10 -12 ) carriers. The associations in the prospective cohort were similar., Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors' research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.Genet Med 18 1, 13-19.

Heterozygous loss-of-function SMAD4 mutations are associated with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. Some carriers exhibit symptoms of both conditions, leading to juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome. Three families have been reported with connective tissue abnormalities. To better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. Twenty-one percent of the patients (7/34) had features suggesting a connective tissue defect: enlarged aortic root (n = 3), aortic and mitral insufficiency (n = 2), aortic dissection (n = 1), retinal detachment (n = 1), brain aneurysms (n = 1), and lax skin and joints (n = 1). Juvenile polyposis-specific findings were almost uniformly present but variable. Ninety-seven percent of the patients had colon polyps that were generally pan-colonic and of variable histology and number. Forty-eight percent of the patients (15/31) had extensive gastric polyposis. Hereditary hemorrhagic telangiectasia features, including epistaxis (19/31, 61%), mucocutaneous telangiectases (15/31, 48%), liver arteriovenous malformation (6/16, 38%), brain arteriovenous malformation (1/26, 4%), pulmonary arteriovenous malformation (9/17, 53%), and intrapulmonary shunting (14/23, 61%), were documented in 76% of the patients. SMAD4 carriers should be managed for juvenile polyposis and hereditary hemorrhagic telangiectasia because symptoms of both conditions are likely yet unpredictable. Connective tissue abnormalities are an emerging component of juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome, and larger studies are needed to understand these manifestations.

Purpose: To assess the impact of a multimodal interdisciplinary course on genetic cancer risk assessment and research collaboration for community-based clinicians. Clinicians are increasingly requested to conduct genetic cancer risk assessment, but many are inadequately prepared to provide these services., Methods: A prospective analysis of 131 participants (48 physicians, 41 advanced-practice nurses, and 42 genetic counselors) from community settings across the United States. The course was delivered in three phases: distance didactic learning, face-to-face training, and 12 months of web-based professional development activities to support integration of skills into practice. Cancer genetics knowledge, skills, professional self-efficacy, and practice changes were measured at baseline, immediate, and 14 months postcourse., Results: Knowledge, skills, and self-efficacy scores were significantly different between practice disciplines; however, postscores increased significantly overall and for each discipline (P < 0.001). Fourteen-month practice outcomes reflect significant increases in provision of genetic cancer risk assessment services (P = 0.018), dissemination of cancer prevention information (P = 0.005) and high-risk screening recommendations (P = 0.004) to patients, patient enrollment in research (P = 0.013), and educational outreach about genetic cancer risk assessment (P = 0.003)., Conclusions: Results support the efficacy of the multimodal course as a tool to develop a genetically literate workforce. Sustained alumni participation in web-based professional development activities has evolved into a distance-mediated community of practice in clinical cancer genetics, modeling the lifelong learning goals envisioned by leading continuing medical education stakeholders.

Purpose: To describe nongenetics clinicians' perceptions and knowledge of cancer genetics and laws prohibiting genetic discrimination, attitudes toward the use of cancer genetic testing, and referral practices., Methods: Invitations to participate were sent to a random stratified sample of California Medical Association members and to all members of California Association of Nurse Practitioners and California Latino Medical Association. Responders in active practice were eligible and completed a 47-item survey., Results: There were 1181 qualified participants (62% physicians). Although 96% viewed genetic testing as beneficial for their patients, 75% believed fear of genetic discrimination would cause patients to decline testing. More than 60% were not aware of federal or California laws prohibiting health insurance discrimination--concern about genetic discrimination was selected as a reason for nonreferral by 11%. A positive attitude toward genetic testing was the strongest predictor of referral (odds ratio: 3.55 [95% confidence interval: 2.24-5.63], P < 0.001) in stepwise logistic regression analyses. The higher the belief in genetic discrimination, the less likely a participant was to refer (odds ratio: 0.72 [95% confidence interval: 0.518-0.991], P < 0.05), whereas more knowledge of genetic discrimination law was associated with comfort recommending (odds ratio: 1.18 [95% confidence interval: 1.11-1.25], P < 0.001) and actual referral (odds ratio: 3.55 [95% confidence interval: 2.24-5.63], P < 0.001)., Conclusion: Concerns about genetic discrimination and knowledge deficits may be barriers to cancer genetics referrals. Clinician education may help promote access to cancer screening and prevention.

Purpose: The impact of genetic cancer risk assessment on communication of cancer risk information within families is not fully known. We compared women's selection of family members for cancer risk communication and perceived barriers to this communication before genetic cancer risk assessment and 6 months afterward., Methods: Mailed surveys were used to collect prospective data from consenting women undergoing genetic cancer risk assessment because of a personal and/or family history of breast or ovarian cancers. Analysis included descriptive statistics, chi-square and McNemar tests, and paired t tests., Results: A total of 122 women met the study criteria. Although risk communications increased with first-degree relatives (84%-90% for females; 53%-62% for males) and decreased with non-first-degree relatives (21%-9%) before and after genetic cancer risk assessment, the degree of change was nonsignificant. The most commonly cited communication barrier was loss of contact (30%). Demographics, personal or family cancer history, and BRCA status did not significantly influence findings., Conclusions: There was a high degree of cancer risk communications with female first-degree relatives, but less so with male first-degree relatives, both before and after genetic cancer risk assessment. For the majority of women, interpersonal barriers did not preclude risk discussions. Further research is needed to identify how best to facilitate risk communication.

Purpose: Genetic cancer risk assessment is an emerging interdisciplinary practice that requires knowledge of genetics and oncology and specialized patient and family counseling skills. There is a growing need for cancer risk assessment practitioners, but most clinicians have inadequate cross-disciplinary training. An interdisciplinary course was developed to promote practitioner-level competency in cancer risk assessment to community-based clinicians. METHODS Participants were competitively selected from a pool of board-certified/eligible genetic counseling, masters-trained advanced practice nursing and physician applicants. Preference was given to clinicians with strong institutional backing practicing in underserved regions. The Continuing Medical Education/Continuing Education Unit-accredited course included didactic lectures, workshops, counseling practicum, and case conferences. Pre- and postcourse knowledge tests measured cancer genetics knowledge. Six month and one-year postcourse practice outcome surveys measured the impact of the program on professional self-efficacy and continued professional development., Results/conclusions: Forty clinicians completed the course (23 genetic counselors, 14 nurses, and three physicians). There was a significant overall increase of 22.6% in postcourse knowledge scores (P < 0.001). Thirty-five (88%) completed prescribed practice development activities. Of 29 respondents to 1-year postcourse survey, 76% reported increased professional self-efficacy; 66% reported increase in number of patients seen, and virtually all indicated interest in additional training. Outcomes demonstrate the value and efficacy of interdisciplinary training in genetic cancer risk assessment targeted to motivated community-based clinicians. Courses such as this can help address the need for competent cancer risk assessment services in communities outside the academic health center.