MRI phenotypes associated with breast cancer predisposing genetic variants, a multisite review.

PURPOSE: Examine MRI phenotypes of breast cancers arising in patients with various pathogenic variants, to assess for imaging trends and associations. METHOD: Multisite retrospective review evaluated 410 patients from 2001 to 2020 with breast cancer and a predisposing pathogenic variant who underwent breast MRI at time of cancer diagnosis. Dominant malignant lesion features were reported, including lesion type (mass versus non-mass enhancement), size, shape, margin, internal enhancement pattern, plus other features. Kruskal-Wallis test, Fisher's exact test, and pairwise comparisons performed comparing imaging manifestations for the most frequent genetic results. RESULTS: BRCA1 (29.5 %) and BRCA2 (25.9 %) variants were most common, followed by CHEK2 (16.6 %), ATM (8.0 %), and PALB2 (6.3 %), with significant associated differences in race/ethnicity (p = 0.040), age at cancer diagnosis (p = 0.005), tumor shapes (p = 0.001), margins (p < 0.001), grade (p < 0.001), internal enhancement pattern (rim enhancement) (p < 0.001), kinetics (washout) (p < 0.001), and presence of necrosis (p < 0.001). CHEK2 and ATM tumors were often lower grade with spiculated margins (CHEK2: 47.1 %, ATM: 45.5 %), rarely exhibiting washout or tumor necrosis (p < 0.001), and were mostly comprised of luminal molecular subtypes (CHEK2: 88.2 %, ATM: 90.9 %). BRCA1 tumors had the highest proportions with round shape (31.4 %), circumscribed margins (24.0 %), rim enhancement (24.0 %), washout (58.7 %), and necrosis (19.8 %), with 47.9 % comprised of triple negative subtype. Bilateral mastectomy was performed in higher proportions of patients with BRCA1 (84.3 %) and BRCA2 (75.5 %) variants compared to others. CONCLUSIONS: Genetic and molecular profiles of breast cancers demonstrate reproducible MRI phenotypes.

Patient uptake of updated genetic testing following uninformative BRCA1 and BRCA2 results.

Advances have dated the genetic testing initially offered to evaluate for hereditary breast and ovarian cancer risks. Previous research has demonstrated that many patients have not updated testing. This study reviewed the incidence of additional analysis after an uninformative BRCA1/2 result and offered updated testing with limited barriers to those who had not completed. After viewing an educational video and providing informed consent, eligible patients were mailed a saliva collection kit to complete an 84-gene hereditary cancer panel at no personal cost. A total of 704 patients had completed BRCA1/2 only testing between 2001 and 2020. Fifteen percent (N = 102) of the 671 patients with an uninformative BRCA1/2 result had already completed expanded testing. Most, 74 of 102 (73%), had been rereferred to medical genetics during a clinical visit related to cancer care. Those who had already completed additional testing were more likely to have a personal history of cancer (92% vs. 79%, p = 0.002) and live locally (p = 0.032). Invitation to complete updated testing through this study was sent to 372 people, and 116 (31%) consented to participate. For 142 of the 256 who did not proceed with testing through the study, proof of receipt of research information was available. In total, 22 pathogenic variants were reported in 21 of the 226 patients with updated testing from before and including our study: ATM (4), CHEK2 (4), LZTR1 (1), MUTYH (3), NBN (1), NF1 (1), NTHL1 (1), PALB2 (4), PMS2 (1), RAD50 (1), and SPINK1 (1). Many potential barriers of retesting were eliminated by removing personal costs or travel requirements. Still, only about 30% of patients agreed to participate, and a significant portion elected not to proceed. Future research could focus on the discovery of other factors that dissuade patients and what measures may better inform them on potential benefits.

Perception, Prevalence, and Prediction of Severe Infection and Post-acute Sequelae of COVID-19.

BACKGROUND: The aim of the study was to assess, characterize, and describe the prevalence and predicting factors of patient-reported severe coronavirus disease 2019 (COVID-19) infection and post-acute sequelae of COVID-19 (PASC). METHODS: We prospectively surveyed patients who received care in our outpatient clinic for COVID-19 from March 13, 2020, through August 17, 2020, and then retrospectively reviewed their electronic health records. We collected data for age, sex, and persistence of symptoms and compared data for hospitalized and nonhospitalized patients. Continuous and categorical variables were summarized, including time from COVID-19 onset, time to resuming normal activities, and length of time away from work. RESULTS: Of those receiving the survey, 437 adult patients with different degrees of severity of COVID-19 illness responded: 77% were between 3 and 6 months from the onset of infection. In total, 34.9% had persistent symptoms, and 11.5% were hospitalized. The most common symptom was fatigue (75.9%), followed by poor sleep quality (60.3%), anosmia (56.8%), dysgeusia (55%), and dyspnea (54.6%). Predicting factors for PASC were female sex and a negative psychological impact of the disease. Age, hospitalization, persistent symptoms, psychological impact (e.g., anxiety and depression), and time missed from work were significantly associated with perception of having severe COVID-19 illness. Hospitalization was not significantly associated with PASC. CONCLUSIONS: Over one-third of patients in our study had PASC. Persistent symptoms correlated with severity of disease and were significantly more common for women, for patients who had psychological symptoms (depression and/or anxiety), and for patients reporting inability to resume normal activities.

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study.

BACKGROUND: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS: Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. CONCLUSIONS: This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

Symptoms and Clinical Outcomes of Coronavirus Disease 2019 in the Outpatient Setting.

Because most cases of coronavirus disease 2019 (COVID-19) are not severe, understanding the epidemiology of mild cases has important clinical implications. We aimed to describe the symptom profile and associated outcomes in a virtual outpatient COVID-19 clinic. We conducted a prospective cohort study from March through June 2020. We included 106 patients with positive results for SARS-CoV-2, followed up until they had 2 sequential negative tests. Exploratory regression analyses identified potential prognostic symptoms or risk factors associated with outcomes, including emergency department (ED) visits, hospitalizations, and time to resolution of viral shedding. The mean (range) patient age was 51 (18-86) years, 50% were men, and 36.5% had at least 1 risk factor, most commonly asthma (16%) and diabetes (10%). Most patients (98.1%) had symptoms-cough (80.4%), fatigue (67.6%), fever (66.0%), headache (49.0%), and ageusia (46.9%). Nine (8.5%) patients were admitted to the ED, 5 (4.7%) were hospitalized, and none died. Asthma (RR = 7.13, P = .001) and being immunocompromised (RR = 3.44, P = .03) were associated with higher risks of adverse outcomes. Asthma (HR = 0.56, P = .04) and early symptoms of ageusia (HR= 0.50, P = .01) or myalgia (HR = 0.63, P = .04) were associated with significantly longer duration of viral shedding. In contrast to reports about severe cases of COVID-19, we found a higher incidence of sinus symptoms, gastrointestinal symptoms, and myalgia and a lower incidence of fever, anosmia, and ageusia among our mild/moderate cases. Asthma and immunocompromised status were associated with adverse outcomes, and asthma and early symptoms of ageusia or myalgia with significantly longer duration of viral shedding.

Intensive Multicomponent Fibromyalgia Treatment: A Translational Study to Evaluate Effectiveness in Routine Care Delivery.

OBJECTIVE: The current study was designed to evaluate the translation of clinical trial outcomes and clinical guidelines for the treatment of fibromyalgia (FM) into an intensive multicomponent clinical program embedded in routine care delivery. The study aimed to assess the adaptation of these recommended strategies into routine clinical care while evaluating their effectiveness and durability in improving functional status and level of distress in a large clinical sample of FM patients. METHODS: Four hundred eighty-nine patients with FM completed a 2-day program that incorporated best practice recommendations for the treatment of FM. Patients completed the Fibromyalgia Impact Questionnaire-Revised, the Center for Epidemiologic Studies Depression Scale, and the Pain Catastrophizing Scale at admission to the program and at follow-up on average 5 months posttreatment. RESULTS: Significant improvements were seen in functional status (p < 0.0001), depressive symptoms (p < 0.0001), and pain catastrophizing (p < 0.0001) after participation in the intensive multicomponent treatment program. CONCLUSIONS: The present study shows that an intensive multicomponent treatment program embedded in routine care delivery is effective in significantly improving functional status and psychological distress in a large sample of FM patients. The significant improvements were durable and maintained at follow-up.

Physiological Responses to Multiple Low-Doses of Bacillus anthracis Spores in the Rabbit Model of Inhalation Anthrax.

Bacillus anthracis spores that are re-aerosolized from surface deposits after initial contamination present significant health risks for personnel involved in decontamination. To model repeated exposure to low dose B. anthracis spores, three groups of seven rabbits were challenged with multiple low-doses of B. anthracis spores 5 days a week for 3 weeks. Mortality, body temperature, heart and respiration rates, hematology, C-reactive protein, bacteremia, and serum protective antigen were monitored for 21 days post-exposure after the last of multiple doses. All rabbits exposed to a mean daily dose of 2.91 × 102 colony forming units (CFU) survived and showed minimal physiological changes attributable to exposure. One of seven rabbits receiving a mean daily dose of 1.22 × 103 CFU died and four of seven receiving a mean daily dose of 1.17 × 104 CFU died. The LD50 was calculated to be 8.1 × 103 CFU of accumulated dose. Rabbits that succumbed to the higher dose exhibited bacteremia and increases above baseline in heart rate, respiration rate, and body temperature. Two rabbits in the mean daily dose group of 1.17 × 104 CFU exhibited clinical signs of inhalation anthrax yet survived. This study provides a description of lethality, pathophysiology, and pathology in a controlled multiple low-dose inhalation exposure study of B. anthracis in the rabbit model. The data suggest that the accumulated dose is important in survival outcome and that a subset of rabbits may show clinical signs of disease but fully recover without therapeutic intervention.

Genomics combined with a protein informatics platform to assess a novel pathogenic variant c.1024 A>G (p.K342E) in OPA1 in a patient with autosomal dominant optic atrophy.

BACKGROUND: Autosomal Dominant Optic Atrophy (ADOA) is caused by mutations in the Optic Atrophy 1 Gene which disrupts the OPA1 protein. This disruption affects the normal function of the protein; impairs fusion of the mitochondrial inner membrane; and prevents normal OPA1 protein degradation. These events cause damage in retinal ganglion cells that could affect the patients with symptoms ranging from none to legally blind. MATERIALS AND METHODS: Our study identifies a missense variant mutation, c.1024 A > G (p.K342E), in OPA1 gene causing ADOA. Diagnosed clinically in three family members and the presence of this mutation was confirmed in two members by genetic testing. Pathogenic variants in OPA1 impact the secondary protein structure and function by causing non-conservative amino acid substitutions. We also modeled this mutation and compared it to the wild type using statistical mechanics. RESULTS AND CONCLUSIONS: The proband's pathogenic variant, c.1024 A > G (p.K342E), is located in the GTPase domain of OPA1 and causes changes in the protein structure by affecting the oligomerization pattern thus resulting in ADOA. Identifying the pathogenic potential of the missense mutations in the OPA1 gene using neoteric protein modeling techniques would help in the early detection of ADOA in patients who have family history of blindness. This action would help in providing early follow up, possible treatment in the future, and genetic counseling. Abbreviations: ADOA: Autosomal Dominant Optic Atrophy; CYCS: Caspase Activator Cytochrome C; OPA1: Optic Atrophy Gene 1; RGC: Retinal Ganglion Cells; VUS: Variant of Uncertain Significance.

Retrospective review of outcomes in patients with DNA-damage repair related pancreatic cancer.

BACKGROUND: Patients with DNA-damage response genes (DDR)-related pancreas cancer (BRCA1/2 or other DNA-damage related genes) may have improved outcomes secondary to increased sensitivity to DNA-damaging drugs (platinum chemotherapy/ poly ADP ribose polymerase (PARP)-inhibitors). However, data is scarce pertaining to outcomes in this subset of patients. Our objective was to retrospectively identify DDR-related pancreas cancer patients and report on clinical outcomes. METHODS: Pancreas cancer patients with a germline pathogenic variant in BRCA1/2 or other DDR gene were identified retrospectively through review of medical records (medical genetics/oncology) and genetic testing results at our institution. Data regarding clinical outcomes, therapy received, and survival was subsequently extracted. RESULTS: A total of 11 patients with pancreas cancer were identified to carry a pathogenic DDR-variant: BRCA1 (3), ATM (4), BRCA2 (2), PALB2 (1) and FANCC (1). Five of these individuals had prior history of other cancers. Clinically these tumors were localized (4), locally advanced (3), and metastatic (4) at diagnosis. Four out of 11 patients were still alive at time of data review. Survival in the 7 patients who had died was 13.7, 140.0, 20.5, 22.3, 23.5, 25.8, and 111.5 months. All patients with advanced disease had exposure to platinum chemotherapy. CONCLUSIONS: Historical survival in patients with advanced and metastatic pancreas cancer is poor. Results of this DDR-subset of patients do show significantly superior outcomes, likely secondary to exposure to platinum drugs. This data, alongside other similar cohorts, would favor the DDR-genes being a predictive marker with improved survival if exposed to these drugs and the new class of drugs, PARP-inhibitors.

Case report expanding the germline AXIN2- related phenotype to include olfactory neuroblastoma and gastric adenoma.

BACKGROUND: Pathogenic AXIN2 variants cause absence of permanent teeth (hypodontia), sparse hair and eye brows (ectodermal dysplasia), and gastrointestinal polyps and cancer. Inheritance is autosomal dominant with variable penetrance. Only twenty- five patients have been reported from five families. A Mayo Clinic pilot program tested 3009 newly diagnosed cancer patients for pathogenic germline variants in 83 hereditary cancer genes, including AXIN2. We found only one patient with a pathogenic AXIN2 variant. CASE PRESENTATION: The proband was a 49 year-old female who came to Otolaryngology clinic complaining of right-sided nasal obstruction. Biopsy of identified nasal polyp revealed olfactory neuroblastoma (esthesioneuroblastoma). Surgical resection with gross, total tumor resection was followed by radiation therapy. The patient enrolled in a clinical pilot of genetic testing and a pathogenic variant in AXIN2, c.1822del (p.Leu608Phefs*81) (NM_004655.3) was found. She was seen in Medical Genetics clinic and found to have a personal history of hypodontia. Her eyebrows, hair, and nails were all normal. She underwent upper endoscopy and colonoscopy. A four mm gastric adenoma was found and removed. CONCLUSIONS: This is the first case reported on a patient with a pathogenic, germline AXIN2 variant and an olfactory neuroblastoma or a gastric adenoma. We propose that these could be features of the AXIN2 phenotype. The known association between gastric adenomas and familial adenomatous polyposis, the other Wnt/beta-catenin disorder, supports the hypothesis that pathogenic AXIN2 variants increase risk as well. As the odds of a chance co-occurrence of a pathogenic AXIN2 variant and an olfactory neuroblastoma are so rare, it is worth exploring potential causation. We are building a clinical registry to expand understanding of the AXIN2 phenotype and request any clinicians caring for patients with pathogenic AXIN2 variants to contact us.

Physiological Responses to a Single Low-Dose of Bacillus anthracis Spores in the Rabbit Model of Inhalational Anthrax.

Credible dose-response relationships are needed to more accurately assess the risk posed by exposure to low-level Bacillus anthracis contamination during or following a release. To begin to fill this knowledge gap, New Zealand White rabbits were implanted with D70-PCT telemetry transmitters and subsequently aerosol challenged with average inhaled doses of 2.86 x 102 to 2.75 x 105 colony forming units (CFU) of B. anthracis spores. Rabbits exposed to a single inhaled dose at or above 2.54 × 104 CFU succumbed with dose-dependent time to death. Death was associated with increases above baseline in heart rate, respiration rate, and body temperature and all rabbits that died exhibited bacteremia at some point prior to death. Rabbits that inhaled doses of 2.06 × 103 CFU or lower survived to the end of the study and showed no or minimal adverse changes in the measured physiological responses in response to the challenge. Moreover, no bacteremia nor toxemia were observed in rabbits that survived to the end of the study. Overall, the data indicate that challenge doses of B. anthracis below the level sufficient to establish systemic infection do not produce observable physiological responses; however, doses that triggered a response resulted in death.

Characterization of a Pathogenic Variant in the ABCD1 Gene Through Protein Molecular Modeling.

BACKGROUND: The ATP-binding cassette, subfamily D, member 1 (ABCD1) protein is a peroxisomal half-transporter that allows for very long chain fatty acid (VLCFA) degradation. Pathogenic variants of ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. METHODS: A newly characterized and suspected pathogenic variant in ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. RESULTS: A case of adult onset adrenomyeloneuropathy (AMN) and a novel ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. CONCLUSIONS: Data fusion from multiple sources was combined in a comprehensive approach yielding an enriched assessment of the patient's disease and prognosis. Molecular modeling was performed on the variant to better characterize its clinical significance and confirm pathogenicity.

Patients' views on variants of uncertain significance across indications.

As genomic sequencing expands into more areas of patient care, an increasing number of patients learn of the variants of uncertain significance (VUSs) that they carry. Understanding the potential psychosocial consequences of the disclosure of a VUS can help inform pre- and post-test counseling discussions. Medical uncertainty in general elicits a variety of responses from patients, particularly in the growing field of medical genetics and genomics. It is important to consider patients' responses to the ambiguous nature of VUSs across different indications and situational contexts. Genetic counselors and other providers ordering genetic testing should be prepared for the possibility of their patients' misinterpretation of such results. Pre-test counseling should include a discussion of the possibility of VUSs and what it would mean for the patient's care and its potential psychosocial impacts. When a VUS is found, post-test counseling should include additional education and a discussion of the variant's implications and medical management recommendations based on the results. These discussions may help temper subjective interpretations, unrealistic views, and decisional regret.

Genomic Observations of a Rare/Pathogenic SMAD3 Variant in Loeys⁻Dietz Syndrome 3 Confirmed by Protein Informatics and Structural Investigations.

Background and objectives: Loeys-Dietz syndrome 3, also known as aneurysms--osteoarthritis syndrome, is an autosomal dominant genetic connective tissue disease caused by pathogenic variants in SMAD3, a transcription factor involved in TGF-ß signaling. This disorder is characterized by early-onset osteoarthritis and arterial aneurysms. Common features include scoliosis, uvula abnormalities, striae, and velvety skin. Materials and Methods: The pathogenicity of a variant of uncertain significance in the SMAD3 gene was evaluated (variant c.220C > T) through personalized protein informatics and molecular studies. Results: The case of a 44-year-old male, who was originally presumed to have Marfan syndrome, is presented. An expanded gene panel determined the probable cause to be a variant in SMAD3, c.220C > T (p.R74W). His case was complicated by a history of stroke, but his phenotype was otherwise characteristic for Loeys-Dietz syndrome 3. Conclusion: This case emphasizes the importance of comprehensive genetic testing to evaluate patients for connective tissue disorders, as well as the potential benefit of utilizing a protein informatics platform for the assessment of variant pathogenicity.

Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasia.

BACKGROUND: Transient receptor potential cation channel subfamily V member 4 (TRPV4) is an ion channel permeable to Ca2+ that is sensitive to physical, hormonal, and chemical stimuli. This protein is expressed in many cell types, including osteoclasts, chondrocytes, and sensory neurons. As such, pathogenic variants of this gene are associated with skeletal dysplasias and neuromuscular disorders. Pathogenesis of these phenotypes is not yet completely understood, but it is known that genotype-phenotype correlations for TRPV4 pathogenic variants often are not present. METHODS: Newly characterized, suspected pathogenic variant in TRPV4 was analyzed using protein informatics and personalized protein-level molecular studies, genomic exome analysis, and clinical study. RESULTS: This statement is demonstrated in the family of our proband, a 47-year-old female having the novel c.2401A>G (p.K801E) variant of TRPV4. We discuss the common symptoms between the proband, her father, and her daughter, and compare her phenotype to known TRPV4-associated skeletal dysplasias. CONCLUSIONS: Protein informatics and molecular modeling are used to confirm the pathogenicity of the unique TRPV4 variant found in this family. Multiple data were combined in a comprehensive manner to give complete overall perspective on the patient disease and prognosis.

Integrative data fusion for comprehensive assessment of a novel CHEK2 variant using combined genomics, imaging, and functional-structural assessments via protein informatics.

The CHEK2 gene and its encoded protein Chk2 have a well-known role in cancers, especially those related to breast cancer mediated through the BRCA1 gene. Additionally Chk2 has a crucial role in DNA repair, apoptosis and the cell cycle, which is why classification of variants of uncertain significance (VUS) is an area highly sought for a better elucidation of the "genomic effect" that results. Because it can often take years before enough clinical data is accumulated, and the costly and expensive functional analysis for individual variants presents a significant hurdle, it is important to identify other tools to help aid in clarifying the impact of specific variants on a protein's function and eventually the patient's health outcome. Here we describe a newly identified CHEK2 variant and analyze with an integrated approach combining genomics (whole exome analysis), clinical study, radiographic imaging, and protein informatics to identify and predict the functional impact of the VUS on the protein's behavior and predicted impact on the related pathways. The observed and analyzed defects in the protein were consistent with the expected clinical effect. Here, we support the use of personalized protein modeling and informatics and further our goal of developing a large-scale protein deposition archive for all protein-level VUS.

Common benign breast concerns for the primary care physician.

Women often visit their primary care physician because of breast concerns such as masses, pain, and nipple discharge. Most breast problems are benign, but it is important to know how to manage these and other breast problems and when to refer patients for further testing.

Physician interpretation of variants of uncertain significance.

A growing number of physicians will interact with genetic test results as testing becomes more commonplace. While variants of uncertain significance can complicate results, it is equally important that physicians understand how to incorporate these results into clinical care. An online survey was created to assess physician self-reported comfort level with genetics and variants of uncertain significance. Physicians were asked to respond to three case examples involving genetic test results. The survey was sent to 488 physicians at Mayo Clinic FL on 8/16/2017. Physicians from all specialties were invited to participate. A total of 92 physicians responded to the survey. Only 13/84 (14.6%) responded to all three case examples with the answer deemed "most correct" by review of literature. Physicians that specialized in cancer were more likely to answer questions appropriately (P = .02). Around half (39/84) of the physicians incorrectly defined a variant of uncertain significance (VUS). Over 75% made a recommendation for genetic testing that was not warranted. Many physicians have never received formal genetics training; however, they will be expected to provide an accurate explanation of the genetic test results and subsequent evidence-based medical management recommendations. These results demonstrate that a substantial proportion of physicians lack a true understanding of the implications a VUS. Utilization of supplemental genetics training programs coupled with increase awareness of genetic services may help to improve patient care.

Patients with pathogenic variants for breast cancer other than BRCA1 and BRCA2: qualitative interviews about health care experiences.

BACKGROUND: Genetic testing for hereditary cancer syndromes has been revolutionized by next-generation sequencing, which allows for simultaneous review of numerous genes. Multigene panels are regularly offered to patients because of their scope and decreased cost and turnaround time. However, many genes included on larger panels have not been studied as extensively as BRCA1 and BRCA2 (BRCA1/2), and their clinical effects are often not as well established. METHODS: We identified patients who received positive test results for pathogenic variants of breast cancer genes from January 2012 through May 2018. We mailed a survey and conducted qualitative interviews to explore the personal and health care experiences of patients with pathogenic variants of BRCA1/2 and patients with "other" (ie, non-BRCA1/2 or PALB2; PTEN; ATM; TP53; NBM, RAD51C; MSH6) variants. We compared the experiences of these patients. RESULTS: Fifty-nine out of 128 individuals responded to the survey (46%). Thirty-two patients had BRCA1/2 variants, and 27 had other variants. (49 women and 10 men; median [range] age, 63 [34-87] years). We interviewed 21 patients (17 women and 4 men; median [range] age, 59.6 [34-82] years). Of the interview participants, ten patients had BRCA1/2 variants, and 11 had non-BRCA1/2 variants. Patients reported receiving poor information about their genetic test results, and they often educated their physicians about their results. Some patients believed that they had been ignored or "brushed off" by health care professionals because non-BRCA1/2 genes are less understood outside the genetics research community. Patients with BRCA1/2 variants had similar problems with health care providers, despite increased awareness and established guidelines about BRCA1/2. CONCLUSIONS: Research is required to understand the clinical significance and proper management of diseases attributable to newly characterized hereditary cancer genes. Additional evaluation of patient and provider education should be at the forefront of efforts to improve patient care.