IMAGING RHEGMATOGENOUS RETINAL LESIONS AND PERIPHERAL VITREORETINAL INTERFACE WITH WIDEFIELD OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: Analyze the peripheral vitreoretinal interface with widefield optical coherence tomography. METHODS: Retrospective chart analysis and widefield optical coherence tomography in 120 consecutive cases of rhegmatogenous pathology. RESULTS: There were 166 lesions in 120 eyes, including 106 horseshoe tears, 22 operculated holes, 30 nonoperculated holes, six giant tears, and two peripheral lamellar defects followed for 6.1 ± 1.2 months. Posterior vitreous detachment was present in all eyes (101/101, 100%) with tears and operculated holes, but only in 5/19 eyes (26.3%) with nonoperculated holes ( P < 0.001). Axial vitreous traction was evident at the anterior edge of horseshoe tears (106/106, 100%), but not the posterior border (18/106, 17%, P < 0.001). Operculated holes located posterior to the vitreous base were free from vitreous traction, displaying a morphology similar to the macular hole. Nonoperculated holes were farther anterior with signs of tangential traction in 23/30 (76.7%) cases. Peripheral vitreoschisis was more often associated with nonoperculated holes (25/30, 83.3%), than horseshoe tears (17/106, 16%; P < 0.001). Horseshoe tears and nonoperculated holes were more often associated with retinal detachment (58/106 [54.7%] and 15/30 [50%], respectively) than operculated holes (5/22, 22.7%), P = 0.023. CONCLUSION: Peripheral vitreoretinal interactions are similar to vitreomaculopathies, with axial and vitreoschisis-related tangential traction playing different roles in different rhegmatogenous pathologies. Peripheral optical coherence tomography improves understanding of pathophysiology and risks of retinal detachment.

Corrigendum: A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: a case report.

[This corrects the article DOI: 10.3389/fonc.2023.1102184.].

Recovery of bacillary layer detachment associated with macula-off rhegmatogenous retinal detachment: Evidence of foveation mechanisms?

Purpose: To describe the mechanisms of postoperative foveal restoration in three patients with bacillary layer detachment (BALAD) associated with macula-off rhegmatogenous retinal detachment. Observations: BALAD associated with macula-off rhegmatogenous retinal detachment presented with two different morphologies: with an intact foveal roof (case 1) and lamellar, with an open foveal roof (cases 2 and 3). In case 1 visual acuity significantly improved and foveal morphology completely restored at postoperative month 6, with a marked increase in foveal thickness. Case 2 presented with a lamellar BALAD in a long-standing retinal detachment, and it was treated with scleral buckling with an unfavourable evolution into a full-thickness hole in the early postoperative period. It was then addressed with internal limiting membrane peeling and inverted flap, which resulted in the resolution of the lesion, but with limited postoperative visual and anatomical recovery. Case 3 lamellar BALAD was directly addressed with pars plana vitrectomy, ILM peeling and inverted flap, with a remarkable foveal anatomical restoration and visual acuity improvement over the follow-up period. Conclusions and importance: The process of foveation may play a key role in the healing process of BALAD associated with rhegmatogenous retinal detachment. Lamellar BALAD should be considered and treated as a FTMH associated with retinal detachment. The two BALAD subtypes may represent different clinical stages of the BALAD spectrum.

COVID-19 pandemic and ophthalmological emergencies: a case-control analysis of the impact of lockdowns in a University Hospital in Lombardy region, Italy.

PURPOSE: To evaluate the incidence of ocular pathologies seen at the ophthalmological emergency department (OED) during the national lockdown in 2020 due to the COVID-19 pandemic and compare it to the corresponding period in 2019. METHODS: Electronic records of patients who presented at the OED of our University Hospital in Varese, Italy during the COVID-19 lockdown were compared with that from the corresponding period in 2019. Records from the spring (2020A) and winter (2020B) lockdowns were compared with each other and with the same periods in 2019 (2019A and 2019B). Statistical analyses were performed by unpaired Student's t-tests, Poisson's regression and Chi-square test. RESULTS: The number of consultations at the OED significantly decreased during the COVID-19 lockdown (p value <.0001). The largest decreases were observed in the youngest (age <15 years: -77.3%) and oldest (age >61 years, -68.5%) age groups. The proportion of men who consulted increased significantly from 61.76% in 2019A to 67.63% in 2020A, and from 54.56% in 2019B to 62.79% in 2020B. A significant reduction in deferrable consultations was also reported (from 943 in 2019 to 335 in 2020; p value <.0001). A statistically significant decrease in the number of consultations involving ocular trauma was also reported despite an increase in its proportion among all consultations for ocular pathologies in 2020. CONCLUSIONS: Our evaluation showed a significant reduction in the number of OED consultations in all deferrable pathologies. Although the incidence of conditions that affect visual function was lower, these were more frequent in the lockdown period. The significant reduction in the number of deferrable consultations highlights the misuse of the OED.

Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study.

BACKGROUND: Germline pathogenic variants (PVs) in BRCA1/2 genes are associated with breast cancer (BC) risk in both women and men. Multigene panel testing is being increasingly used for BC risk assessment, allowing the identification of PVs in genes other than BRCA1/2. While data on actionable PVs in other cancer susceptibility genes are now available in female BC, reliable data are still lacking in male BC (MBC). This study aimed to provide the patterns, prevalence and risk estimates associated with PVs in non-BRCA1/2 genes for MBC in order to improve BC prevention for male patients. METHODS: We performed a large case-control study in the Italian population, including 767 BRCA1/2-negative MBCs and 1349 male controls, all screened using a custom 50 cancer gene panel. RESULTS: PVs in genes other than BRCA1/2 were significantly more frequent in MBCs compared with controls (4.8% vs 1.8%, respectively) and associated with a threefold increased MBC risk (OR: 3.48, 95% CI: 1.88-6.44; p < 0.0001). PV carriers were more likely to have personal (p = 0.03) and family (p = 0.02) history of cancers, not limited to BC. PALB2 PVs were associated with a sevenfold increased MBC risk (OR: 7.28, 95% CI: 1.17-45.52; p = 0.034), and ATM PVs with a fivefold increased MBC risk (OR: 4.79, 95% CI: 1.12-20.56; p = 0.035). CONCLUSIONS: This study highlights the role of PALB2 and ATM PVs in MBC susceptibility and provides risk estimates at population level. These data may help in the implementation of multigene panel testing in MBC patients and inform gender-specific BC risk management and decision making for patients and their families.

Refinement of the assignment to the ACMG/AMP BS3 and PS3 criteria of eight BRCA1 variants of uncertain significance by integrating available functional data with protein interaction assays.

The clinical screening of cancer predisposition genes has led to the identification of a large number of variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is limited by the amount of necessary data, which are difficult to obtain for rare variants. The guidelines for variant interpretation of the American College of Medical Genetics and Genomics along with the Association for Molecular Pathology (ACMG/AMP) state that "well-established" functional studies provide strong support of a pathogenic or benign impact (criteria PS3 and BS3, respectively) and can be used as evidence type to reach a final classification. Moreover, the Clinical Genome Resource Sequence Variant Interpretation Working Group developed rule specifications to refine the PS3/BS3 criteria. Recently, Lira PC et al. developed the "Hi Set" approach that generated PS3/BS3 codes for over two-thousands BRCA1 VUS. While highly successful, this approach did not discriminate a group of variants with conflicting evidences. Here, we aimed to implement the outcomes of the "Hi-set" approach applying Green Fluorescent Protein (GFP)-reassembly assays, assessing the effect of variants in the RING and BRCT domains of BRCA1 on the binding of these domains with the UbcH5a or ABRAXAS proteins, respectively. The analyses of 26 clinically classified variants, including 13 tested in our previous study, showed 100% sensitivity and specificity in identifying pathogenic and benign variants for both the RING/UbcH5a and the BRCTs/ABRAXAS interactions. We derived the strength of evidences generated by the GFP-reassembly assays corresponding to moderate for both PS3 and BS3 criteria assessment. The GFP-reassembly assays were applied to the functional characterization of 8 discordant variants from the study by Lyra et al. The outcomes of these analyses, combined with those reported in the "Hi Set" study, allowed the assignment of ACMG/AMP criteria in favor or against pathogenicity for all 8 examined variants. The above findings were validated with a semi-quantitative Mammalian Two-Hybrid approach, and totally concordant results were observed. Our data contributes in shedding light on the functional significance of BRCA1 VUS and on their clinical interpretation within the ACMG/AMP framework.

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report.

The widespread adoption of gene panel testing for cancer predisposition is leading to the identification of an increasing number of individuals with clinically relevant allelic variants in two or more genes. The potential combined effect of these variants on cancer risks is mostly unknown, posing a serious problem for genetic counseling in these individuals and their relatives, in whom the variants may segregate singly or in combination. We report a female patient who developed triple-negative high grade carcinoma in the right breast at the age of 36 years. The patient underwent bilateral mastectomy followed by combined immunotherapy and chemotherapy (IMpassion030 clinical trial). Two years later she developed a skin recurrence on the right anterior chest wall. Despite intensive treatment, the patient died at 40-year-old due to disease progression. Gene panel testing of patient's DNA revealed the presence of a protein truncating variant in ATM [c.1672G>T; p.(Gly558Ter)] and of a not previously reported variant in the BRCA1 exon 22 donor splice site [c.5406+6T>C], whose clinical significance was unknown. The analysis of patient's RNA revealed the up-regulation of two alternative BRCA1 mRNA isoforms derived from skipping of exon 22 and of exons 22-23. The corresponding predicted protein products, p.(Asp1778GlyfsTer27) and p.(Asp1778_His1822del) are both expected to affect the BRCA1 C Terminus (BRCT) domain. The two variants were observed to co-occur also in the proband's brother who, in addition, was heterozygous for a common variant (c.4837A>G) mapped to BRCA1 exon 16. This allowed to ascertain, by transcript-specific amplification, the lack of functional mRNA isoforms expressed by the c.5406+6T>C allele and provided evidence to classify the BRCA1 variant as pathogenic, according to the guidelines of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium. To our knowledge, excluding two cases detected following the screening of population specific recurrent variants, only one ATM/BRCA1 double heterozygote has been reported in the literature, being the case here described the one with the youngest age at cancer onset. The systematic collection of cases with pathogenic variants in more than one cancer predisposition gene is needed to verify if they deserve ad hoc counseling and clinical management.

Role of Vitrectomy in Nontractional Refractory Diabetic Macular Edema.

BACKGROUND: Currently, the gold standard of diabetic macular edema (DME) treatment is anti-vascular endothelial growth factor (VEGF) injections, although a percentage of patients do not respond optimally. Vitrectomy with or without internal limiting membrane (ILM) peeling is a well-established treatment for DME cases with a tractional component while its role for nontractional cases is unclear. The aim of this study is to evaluate the role of vitrectomy with or without ILM peeling in nontractional refractory DME. METHODS: We performed a retrospective review of twenty-eight eyes with nontractional refractory DME treated with vitrectomy at San Giuseppe Hospital, Milan, between 2016 and 2018. All surgeries were performed by a single experienced vitreoretinal surgeon. In 43.4% of cases, the ILM was peeled. Best corrected visual acuity and optical coherence tomography (OCT) scans were assessed preoperatively and at 6, 12, and 24 months post-vitrectomy. RESULTS: The mean central macular thickness improved from 413.1 ± 84.4 to 291.3 ± 57.6 µm at two years (p < 0.0001). The mean logarithm of the minimum angle of resolution logMAR best-corrected visual acuity (BCVA) improved after two years, from 0.6 ± 0.2 to 0.2 ± 0.1 (p < 0.0001). We found no difference between ILM peeling vs. no ILM peeling group in terms of anatomical (p = 0.8) and visual outcome (p = 0.3). Eyes with DME and subfoveal serous retinal detachment (SRD) at baseline had better visual outcomes at the final visit (p = 0.001). CONCLUSIONS: We demonstrated anatomical and visual improvement of patients who underwent vitrectomy for nontractional refractory DME with and without ILM peeling. Improvement was greater in patients presenting subretinal fluid preoperatively.

Peripheral Intravascular Catheter-Assisted Sutureless Scleral Fixation of Three-Piece Intraocular Lenses: A Novel Technique.

PURPOSE: To describe and report the anatomical and functional outcomes of a novel sutureless peripheral intravascular catheter (PIVC)-assisted scleral fixation of three-piece IOL. METHODS: A retrospective chart review of all patients who underwent scleral fixation surgery performed by a single surgeon was conducted. In all cases, a novel scleral fixation technique of three-piece IOL was performed with the aid of a 24-gauge PIVC cannula. Patients were followed up at postoperative months 1, 3, and 6. RESULTS: Thirteen eyes of 12 patients were included in the analysis. Preoperatively, mean best-corrected visual acuity was 1.26 ± 0.82 LogMar (20/364 Snellen Equivalent), and it improved significantly at all follow-up endpoints being of 0.52 ± 0.25 LogMar at 1 month (20/66 Snellen Equivalent, P = 0.02), 0.4 ± 0.22 LogMar at 3 months (20/50 Snellen Equivalent, P = 0.007) and 0.37 ± 0.2 LogMar (20/47 Snellen Equivalent, P = 0.008) at 6 months postoperatively. No serious intraoperative or postoperative complications were registered. Postoperatively, there were no cases of conjunctival erosions. Over the follow-up period, in all the included cases, the IOL remained centered and stable. CONCLUSION: The PIVC-assisted scleral fixation technique may be a safe and reliable surgical option for secondary IOL placement in cases of insufficient capsular support.

Central Serous Chorioretinopathy in a 14-year-old atopic boy: a case report.

BACKGROUND: Corticosteroids are widely used in medicine. Few cases of central serous chorioretinopathy (CSC) have been reported following topical corticosteroid administration. We describe the first case of pediatric CSC related to topical corticosteroid administration. CASE PRESENTATION: A 14-year-old boy presented with decreased vision, pigment epithelial detachments, and serous retinal detachments in the right eye after starting treatment for atopic dermatitis with Betamethasone Valerate 0.1% topical ointment. His condition resolved 2 weeks after discontinuing the steroid and administering Bromfenac 0.9 mg/ml eyedrops. CONCLUSIONS: Although the pathogenesis of CSC is poorly understood, ophthalmologists should be informed about the potential link between CSC and topical corticosteroid treatment, and they should be aware that CSC might, albeit infrequently, affect children.

Presumed sympathetic ophthalmia following scleral buckling surgery: A case report and review of the literature.

PURPOSE: To report a case of presumed sympathetic ophthalmia (SO) following scleral buckling (SB) surgery and to discuss the possible pathogenesis of this condition by reviewing the current evidence on this subject. METHODS: Case report and narrative review of the literature; our case was imaged with spectral-domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCTA), fundus autofluorescence (FAF), fluorescein angiography (FFA) and indocyanine green angiography (ICGA). RESULTS: A 55-year-old man presented with a macula on rhegmatogenous retinal detachment which was treated with 360° SB surgery, subretinal fluid drain (SRFD), cryopexy and pneumoretinopexy. Due to failure of the primary surgery, a second procedure was performed the day after with the explant of the prior buckle and the implant of a wider circumferential element. At three months from surgery, the patient complained of severe bilateral vision loss. Multimodal imaging revealed bilateral, multi-focal exudative retinal detachments and choroidal swelling. A diagnosis of presumed SO was made and the patient was treated with a combination of steroid and immunosuppressive drugs. The clinical picture completely resolved at postoperative month 12. CONCLUSION: SO may be a rare complication of SB surgery. In our case, early recognition and prompt immunosuppressive treatment achieved good long-term clinical results.

Full-Thickness Macular Hole: Are Supra-RPE Granular Deposits Remnants of Photoreceptors Outer Segments? Clinical Implications.

PURPOSE: To describe the presence of specific morphological characteristics of idiopathic, full-thickness macular hole (MH) potentially influencing postoperative best corrected visual acuity (BCVA) and surgical outcomes. DESIGN: Retrospective, multicenter and interventional case series. METHODS: Clinical charts and multimodal imaging pictures of 149 eyes of 143 consecutive patients diagnosed with MH, treated surgically and with a minimum follow-up of 12 months, were reviewed. RESULTS: Supra-retinal pigment epithelium (RPE) granular deposits were diagnosed in 121 of 149 eyes (81.2%). A smooth morphology was identified in 58 of 149 eyes (38.9%), whereas a bumpy border was present 91 of 149 eyes (61.1%). Photoreceptor disruption was mainly located close to the MH aperture. In 8% of the included cases, preoperative anatomical progression from smooth to bumpy morphology was noted. The presence of supra-RPE granular deposits was a significant predictor of lower postoperative BCVA only in univariate analysis (P < .001). The presence of a bumpy border was significantly correlated with lower postoperative BCVA in both univariate and multivariate analysis (P < .001). BCVA gain was significantly lower in MH with bumpy borders (P < .001). A bumpy border was also significantly associated with poor postoperative anatomical restoration (P < .001). CONCLUSIONS: Supra RPE-granular deposits and a bumpy morphology may be indicators of photoreceptor disruption in MH. A bumpy morphology may suggest deeper and potentially irreversible photoreceptor damage, and may negatively influence both functional and anatomical recovery.

Gene expression-based dissection of inter-histotypes, intra-histotype and intra-tumor heterogeneity in pediatric tumors.

Intra-tumor heterogeneity (ITH) fosters tumor evolution, resistance to therapy, and relapse. Recently, many evidence have been accumulated on the occurrence of genetic ITH in pediatric cancers. With this study we aimed to address the downstream effects that genetic and epigenetic ITH, and tumor-microenvironment interactions may produce within a tumor mass. To this aim, we investigated by high-throughput gene expression multiple samples of 5 hepatoblastomas, 5 neuroblastomas, 5 rhabdomyosarcomas, and 5 Wilms tumors. Principal component analysis, single sample hallmark gene sets analysis, and weighted gene co-expression network analysis were performed on gene expression data. We observed that the different tumors clustered by histotype, and then by case, and in addition, a variable degree of ITH was visible in all the investigated cases. The ITH highlighted in this study can represent a challenge in tumor treatment since we demonstrated that different druggable hallmarks and targets may be heterogeneously present within the same tumor mass, and this can potentially lead to therapeutic failure. Despite this heterogeneity, we could highlight some commonalities among the different histotypes investigated, supporting the feasibility to move in the clinic from a histotype-driven to a target-driven, sometimes agnostic, approach at least in some cases.

Glaucoma and Driving License: How to Identify Patients at Risk of Revocation.

Aim: To identify clinical criteria that are easily achievable with follow-up tests and can identify subjects not suitable for driving. Patients and methods: We recruited 194 subjects with a clear diagnosis of glaucoma, with no other conditions that could affect the visual field (VF), and who performed a reliable VF examination. All patients underwent a full ophthalmologic evaluation and a questionnaire considering driving habits. An integrated visual field (IVF) was built using both monocular VF charts; the number of missed points (NoMP) within the central 20°, the average sensitivity (AS), and the better eye mean deviation (BEMD) were evaluated. Results: A total of 128 subjects showed a valid driving license (DL); 61.7% of drivers did not show missed points within the central 20° of the IVF, 27.4% presented one to three missed points, and 10.9% had four or more missed points. Best corrected visual acuity (BCVA) was highly above the legal criteria.Stratifying drivers by their BEMD (-7, -10, and -14 dB), we confirmed that the BEMD decrease corresponds to an increased NoMP and a decreased AS. Conclusion: Better eye mean deviation can be useful in clinical practice to identify patients at increased risk of being unsuitable for driving. Nevertheless, it is important to set specific cut-offs based on on-road driving performance. IVF evaluation may also be implemented in perimeter analysis software so that the composition of IVF, the BEMD, and the AS could directly describe the patient's binocular VF, excluding recourse to the Esterman visual field test (EVFT). Clinical significance: This new methodology will allow every physician-not just ophthalmologists-even if not an expert in evaluating a VF test, in assessing the ability to drive of glaucomatous patients. How to cite this article: Landini L, Donati S, Digiuni M, et al. Glaucoma and Driving License: How to Identify Patients at Risk of Revocation. J Curr Glaucoma Pract 2022;16(2):117-123.

Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.

Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.

The Impact of Mediterranean Dietary Intervention on Metabolic and Hormonal Parameters According to BRCA1/2 Variant Type.

The female carriers of BRCA1/2 pathogenic variants (mutations) face a high lifetime risk of developing breast and/or ovarian cancer. However, the risk may differ depending on various genetic and non-genetic elements, including metabolic and hormonal factors. We previously showed that a 6-month Mediterranean dietary intervention trial reduced body weight and the levels of insulin-like growth factor I and other metabolic factors in BRCA mutation carriers. We also found that higher baseline levels of glucose and insulin were significantly associated with BRCA loss-of-function (LOF) variants. In this study, we evaluated whether the BRCA mutation type influences in a different way the metabolic and hormonal response to the dietary intervention in 366 female carriers. The LOF variant carriers randomized in the intervention group (IG) showed significantly higher changes in most considered parameters compared to the control group (CG). The nonsynonymous variant carriers in the IG showed similar changes, but none of them were statistically significant. Performing the "delta" analysis of differences (intention-to-treat analysis), we observed that in LOF variant carriers, the reduction of insulin levels was significantly more pronounced that in nonsynonymous variant carriers. These findings suggest that the changes in insulin levels might be modulated by a different response to the dietary intervention mediated by BRCA LOF variants.

Evidence-based efficacy of methotrexate in adult Crohn's disease in different intestinal and extraintestinal indications.

Introduction: Methotrexate (MTX) is included in the therapeutic armamentarium of Crohn's disease (CD), although its positioning is currently uncertain in an era in which many effective biological drugs are available. No systematic reviews or meta-analysis have stratified the clinical outcomes of MTX according to the specific clinical scenarios of its use. Methods: Medline, PubMed and Scopus were used to extract eligible studies, from database inception to May 2021. A total of 163 studies were included. A systematic review was performed by stratifying the outcomes of MTX according to formulation, clinical indication and criteria of efficacy. Results: The use of MTX is supported by randomized clinical trials only in steroid-dependent CD, with similar outcomes to thiopurines. The use of MTX in patients with steroid-refractoriness, failure of thiopurines or in combination with biologics is not supported by high levels of evidence. Combination therapy with biologics can optimize the immunogenic profile of the biological drug, but the impact on long-term clinical outcomes is described only in small series with anti-TNFα. Other off-label uses, such as fistulizing disease, mucosal healing, postoperative prevention and extraintestinal manifestations, are described in small uncontrolled series. The best performance in most indications was shown by parenteral MTX, favouring higher doses (25 mg/week) in the induction phase. Discussion: Evidence from high-quality studies in favour of MTX is scarce and limited to the steroid-dependent disease, in which other drugs are the leading players today. Many limitations on study design have been found, such as the prevalence of retrospective underpowered studies and the lack of stratification of outcomes according to specific types of patients and formulations of MTX. Conclusion: MTX is a valid option as steroid-sparing agent in steroid-dependent CD. Numerous other clinical scenarios require well-designed clinical studies in terms of patient profile, drug formulation and dosage, and criteria of efficacy.

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.

PURPOSE: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. METHODS: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. RESULTS: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. CONCLUSION: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.