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.

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.

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.

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.

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.

Late onset asymptomatic pancreatic neuroendocrine tumor - A case report on the phenotypic expansion for MEN1.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome associated with several endocrine as well as non-endocrine tumors and is caused by mutations in the MEN1 gene. Primary hyperparathyroidism affects the majority of MEN1 individuals by age 50 years. Additionally, MEN1 mutations trigger familial isolated hyperparathyroidism. We describe a seemingly unaffected 76-year-old female who presented to our Genetics Clinic with a family history of primary hyperparathyroidism and the identification of a pathogenic MEN1 variant. CASE PRESENTATION: The patient was a 76 year-old woman who appeared to be unaffected. She had a family history of a known MEN1 pathogenic variant. Molecular testing for the known MEN1 mutation c.1A > G, as well as, biochemical testing, MRI of the brain and abdomen were all performed using standard methods. Molecular testing revealed our patient possessed the MEN1 pathogenic variant previously identified in her two offspring. Physical exam revealed red facial papules with onset in her seventies, involving her cheeks, nose and upper lip. Formerly, she was diagnosed with rosacea by a dermatologist and noted no improvement with treatment. Clinically, these lesions appeared to be facial angiofibromas. Brain MRI was normal. However, an MRI of her abdomen revealed a 1.5 cm lesion at the tail of the pancreas with normal adrenal glands. Glucagon was mildly elevated and pancreatic polypeptide was nearly seven times the upper limit of the normal range. The patient underwent spleen sparing distal pancreatectomy and subsequent pathology was consistent with a well-differentiated pancreatic neuroendocrine tumor (pNET). CONCLUSIONS: Age-related penetrance and variable expressivity are well documented in families with MEN1. It is thought that nearly all individuals with MEN1 manifest disease by age 40. We present a case of late-onset MEN1 in the absence of the most common feature, primary hyperparathyroidism, but with the presence of a pNET and cutaneous findings. This family expands the phenotype associated with the c.1A > G pathogenic variant and highlights the importance of providing comprehensive assessment of MEN1 mutation carriers in families that at first blush may appear to have isolated hyperparathyroidism.

Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: a 5-year follow-up.

PURPOSE: This study was designed to explore whether zoledronic acid could prevent expected loss of bone mineral density (BMD) in postmenopausal women with pre-existing osteopenia or osteoporosis who were initiating adjuvant letrozole therapy for primary breast cancer. METHODS: Between June 2006 and July 2007, 60 postmenopausal women with estrogen and/or progesterone receptor-positive breast cancer and a BMD T-score ≤-2.0 were enrolled. Participants received letrozole 2.5 mg and vitamin D 400 IU daily, calcium 500 mg twice daily, and zoledronic acid 4 mg every 6 months for a maximum of 5 years or until disease progression. BMD at the lumbar spine and femoral neck was recorded at the start of the study and annually for 5 years. Patients were evaluated for fractures every 6 months for the duration of the trial. RESULTS: After 5 years, mean BMD increased significantly by 11.6% (p = 0.01) at the lumbar spine and by 8.8% (p = 0.01) at combined sites. Femoral neck BMD increased by 4.2%, although this was not significant (p = 0.23). At the end of the trial, BMDs were consistent with osteoporosis in 7 % and osteopenia in 36% of the patients. A total of six fractures were reported after 417 individual assessments. CONCLUSIONS: Zoledronic acid appears to prevent further bone loss in postmenopausal breast cancer patients with osteopenia and osteoporosis starting treatment with letrozole. These findings were maintained at 5 years and support concurrent initiation of bisphosphonate and aromatase inhibitor therapy in this high-risk population.

5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial.

BACKGROUND: Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results. METHODS: A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of <-2.0 or fracture. RESULTS: The incidence of a 5% decrease in the total lumbar spine bone mineral density at 5 years was 10.2% in the upfront treatment arm versus 41.2% in the delayed treatment arm (P<.0001). A total of 41 patients in the delayed treatment arm were eventually started on ZA. With the exception of increased NCI Common Toxicity Criteria (CTC) grade 1/2 elevated creatinine and fever in the patients treated on the upfront arm and cerebrovascular ischemia among those in the delayed treatment arm, there were no significant differences observed between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront treatment arm (2 vs 8 cumulative cases), although this difference was not found to be statistically significant. Bone fractures occurred in 24 patients in the upfront treatment arm versus 25 patients in the delayed treatment arm. CONCLUSIONS: Immediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms.

Educational Intervention in Primary Care Residents' Knowledge and Performance of Hepatitis B Vaccination in Patients with Diabetes Mellitus.

OBJECTIVES: Although guidelines recommend hepatitis B virus (HBV) immunization for adults with diabetes mellitus (DM), vaccination rates remain low. Our aim was to evaluate knowledge and practice regarding HBV and to assess the effectiveness of a multifaceted educational program. METHODS: Primary care residents (n = 244) at three academic institutions were surveyed about various aspects of HBV. Residents at one training program were then randomly assigned to an educational intervention (E) (n = 20) and control group (C) (n = 19). The E group received a focused didactic lecture and periodic e-mail reminders with immediate feedback. We compared knowledge scores before and after the intervention. Chart audits were conducted to evaluate the residents' behavior. RESULTS: A total of 103 (42%) residents responded to the survey. The survey indicated that residents lacked the necessary knowledge and risk assessment skills concerning HBV in patients with DM. In the controlled trial of the E intervention, both groups had similar baseline knowledge scores. The E group had a significant increase in the immediate postintervention knowledge scores from a mean of 29% at baseline to 70% (P < 0.001) that was sustained 6 months postintervention (65%; P < 0.001). In the C group, 6-month postintervention scores were not different from baseline (38% vs 29%). No significant differences were observed in documentation skills. CONCLUSIONS: A combined educational program was effective in enhancing knowledge about HBV and vaccination in DM but had limited influence on physicians' practice. Further study incorporating system changes along with educational initiatives is required to improve clinical practice.

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.

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.

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.

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.

Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen-N03CC.

Postmenopausal women with breast cancer (BC) are at increased risk for bone loss. Bisphosphonates improve bone mineral density (BMD) in normal postmenopausal women. The purpose of this study was to determine if immediate treatment with zoledronic acid preserves BMD in postmenopausal women with BC starting letrozole after tamoxifen. Postmenopausal women with BC completing tamoxifen were treated with daily letrozole 2.5 mg/vitamin D 400 I.U., calcium 500 mg twice daily and were randomized to upfront or delayed zoledronic acid 4 mg every 6 months. Patients in the delayed arm were only given zoledronic acid if they developed a post-baseline BMD T score <-2.0 or had a fracture. The primary endpoint was the mean percent change in lumbar spine (LS) BMD at 1 year. About 558 women enrolled; 395 provided 1 year BMD data. The upfront arm experienced a mean change of +3.66% in LS BMD versus -1.66% for the delayed group (P < 0.001). Changes at the femoral neck/total hip were also greater for the upfront versus delayed arms (P < 0.001; P < 0.001) with differences persisting at 2 years. Patients in the delayed arm were more likely to experience a clinically meaningful 5% loss of BMD at all sites versus the upfront zoledronate group. Patients in the upfront arm were slightly more likely to report limb edema, fatigue, fever, nausea and jaw osteonecrosis(1%). Upfront zoledronic acid prevents bone loss in postmenopausal women with BC starting letrozole after tamoxifen.

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.

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.

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.

Incidence of Pathogenic Variants in Those With a Family History of Pancreatic Cancer.

Discovery of a hereditary cancer syndrome can be one of the factors that determine whether a healthy individual completes pancreas cancer screening or whether an individual with cancer receives certain chemotherapies. Retrospective review was completed to determine the likelihood of detection of a pathogenic variant causing a hereditary cancer syndrome based on personal and family history. Study was completed through the hereditary cancer clinic at Mayo Clinic Florida over a 6 year period, 1/2012 through 1/2018. All participants were referred based on suspicion for a hereditary cancer syndrome based on personal and/or family history. Patients' personal oncologic history at time of consultation was recorded, as well as, cancer diagnoses in the family history and the number of family members with a history of pancreas cancer. Test result and gene name, if variant was pathogenic or likely pathogenic, were noted as well. A total of 2,019 patients completed genetic testing during study period. Personal history of cancer included a variety of primaries, including breast (N = 986), ovarian (N = 119), colon (N = 106), prostate (N = 65), and pancreas (N = 59). A positive result was discovered in 11% of the total group. Two hundred and eighty five reported a family history of pancreas cancer. The incidence of pathogenic variants was 13% (37/285) in those with any family history and 23% (13/56) in those with two or more relatives with pancreatic cancer. Those with multiple relatives with pancreatic cancer were significantly more likely to carry a pathogenic variant than those with a personal history of breast cancer under the age of 45 (23.2 vs. 11.9%, p = 0.02). Presence of multiple family members with a reported history of pancreatic cancer significantly increased the likelihood that a pathogenic variant would be identified in the patient even over other significant risk factors, like personal history of early onset breast cancer.

Personalized molecular modeling for pinpointing associations of protein dysfunction and variants associated with hereditary cancer syndromes.

BACKGROUND: Although the process of reclassification of a variant of uncertain significance can be complex, they are commonly detected through molecular testing. It often takes years before enough clinical data are acquired, and it can be costly and time-consuming to perform functional analysis of a single variant. It is important that other tools are developed to aid in clarifying how a specific genetic variant impacts a protein's function, and ultimately the health of the patient. METHODS: Two more newly characterized, suspected pathogenic variants in NBN and PTEN were analyzed through personalized protein modeling. Comparisons between the wild-type and altered protein were studied using simulations, genomic exome analysis, and clinic study. RESULTS: Modeling of the new NBN and PTEN protein structures suggested loss of essential domains important for normal enzymatic function for these personalized genomic examples which matched the clinical findings. CONCLUSION: The defects detected through modeling were consistent with the expected clinical effect. Personalized protein modeling is another tool for determination of correct variant classification, which can become further useful through construction of deposition archive.