Background:For many evidence criteria within v3.0 of the ACMG/AMP guidelines, methodologies have been developed to empower their use outside the stipulated evidence strengths. However, no such methodology has been established for case-control data (PS4). With the release of large-scale unselected case-control datasets and expansion of nationally-collected laboratory datasets enriched for pathogenic variant carriers, there is potential to combine datasets across ascertainment contexts in a more quantitative manner using novel likelihood ratio tools. Methods:Using our published PS4-LR-Calculator, we calculated a combined log likelihood ratio (PS4-LLR) across five datasets (three unselected, and two enriched), and estimated enrichment of pathogenic variants in clinically-ascertained laboratory data using truncating variant prevalence. Results:Data were combined for 10,817 missense variants from 325,345 female breast cancer patients and 671,006 controls of Western European ancestry for five breast cancer susceptibility genes (BRCA1, BRCA2, PALB2, ATM, CHEK2). A combined LLR was produced for 4,690 missense variants; 927 variants received evidence towards pathogenicity (LLR≥ 1), and 3,242 received evidence towards benignity (LLR≤ -1). Conclusion:This flexible, variant-level methodology combines nationally-collected 'enriched' datasets with unselected case-control cohorts, expanding the available information for case-control analysis, boosting power, enabling exploration of atypical penetrance and empowering variant classification.

Abstract Cancer Variant Interpretation Group UK was established in 2017 in response to the publication of the 2015 ACMG/AMP v3 guidance for the interpretation of sequence variants. Its initial purpose was to ensure consistency in the UK clinical-laboratory community implementation of ACMG/AMP v3 guidance for cancer susceptibility genes (CSGs). Still convening for monthly national meetings, the remit of CanVIG-UK now encompasses additional activities delivered under the following objectives: Creation of a national multidisciplinary professional network and regular forum. Delivery of training and education. Establishment of a consensus approach to the fundamentals of variant interpretation in cancer susceptibility genes. Development and ratification of gene-specific frameworks for variant interpretation for cancer susceptibility genes. Development and maintenance of an online platform to facilitate information sharing and variant interpretation within the UK clinical-laboratory community. Facilitation of UK contribution to international variant interpretation endeavours. A survey of CanVIG-UK members evaluating the impact of these activities conducted in November 2025 had 163 responses, including 113 clinical scientists/trainees and 27 Clinical Genetics consultants/trainees. The utility of the CanVIG-UK consensus recommendations for variant interpretation in cancer susceptibility genes was highly rated, with 89/145=61.4% of survey respondents reporting using the guidance at least weekly (≥4 times/month) and 124/128=96.9% rating it as extremely/very useful. The usage frequency and utility of the gene-specific guidance reported by survey respondents were similar to those reported for the main consensus specification. Both qualitative and quantitative survey responses clearly demonstrate the value of the CanVIG-UK activities to the clinical-diagnostic community. Key messages What is already known on this topic: Cancer Variant Interpretation Group UK (CanVIG-UK) is a national subspeciality multidisciplinary network first established in 2017. It brings together members of the UK clinical-laboratory community to improve accuracy and consistency in the interpretation of variants in cancer susceptibility genes (CSG) What this study adds: this article presents the results of a survey of CanVIG-UK members, demonstrating the impact of CanVIG-UK activities on their services, as well as a review of progress in the six updated objectives of CanVIG-UK How this study might affect research, practice or policy: this article presents current priorities and practices and potential future directions for variant interpretation in CSGs across the UK and Republic of Ireland

BACKGROUND:All breast cancer (BC) patients have a risk of developing contralateral BC (CBC). This will be higher in women carrying a BC susceptibility gene pathogenic variant (PV), but specific risk estimates are lacking. We addressed this in a study-level meta-analysis of two large, recent cohort studies that used Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES) project and Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium data. METHODS:We used population risks from the Netherlands to estimate 10-year cumulative CBC risks for BRCA1, BRCA2, PALB2, CHEK2, and ATM PV carriers. We estimated pooled hazard ratios (HRs) in meta-analyses using the generic inverse-variance method and assuming random effects. We stratified by first BC estrogen receptor (ER) status. RESULTS:Among 462 BRCA1, 590 BRCA2, 796 CHEK2, 297 PALB2, and 345 ATM PV carriers, we estimated 10-year cumulative CBC risks of 10.1% (95% confidence interval (CI):7.5-13.6%) for BRCA1, 10.2% (95%CI:7.4-13.9%) for BRCA2, 7.1% (95%CI:3.4-14.3%) for PALB2, 8.0% (95%CI:5.7-11.1%) for CHEK2 (any PV), 8.5% (95%CI:5.9-12.3%) for CHEK2 del.1100 C, and 4.5% (95%CI:2.5-8.0%) for ATM PV carriers. We found elevated HRs in BRCA1 (HR:2.8, 95%CI:2.1-3.6), BRCA2 (HR:2.8, 95%CI:2.1-3.7), and CHEK2 PV carriers (all PVs: HR:2.1, 95%CI:1.6-2.9. del.1100 C PVs only: HR:2.3, 95%CI:1.6-3.3). We found no significantly elevated risks in PALB2 (HR:1.9, 95%CI:0.9-3.8) or ATM (HR:1.2, 95%CI:0.7-2.1) PV carriers. We saw increased risks in BRCA1/2 and CHEK2 PV carriers following ER-positive BC, and in BRCA1/2 and PALB2 PV carriers following ER- negative BC. CONCLUSION:BC survivors carrying BRCA1, BRCA2, and CHEK2 PVs and ER-negative BC survivors carrying PALB2 PVs are at two-fold or higher CBC risks. These estimates may assist clinical decision making for management of the contralateral breast.

BACKGROUND:The Testicular Cancer Consortium (TECAC) was established in 2012 and is comprised of researchers from over 25 centers in Europe and North America. TECAC's overarching goal is to investigate the genetic susceptibility of testicular germ cell tumors (TGCT) to better understand their biology, impact prevention strategies, and inform treatment decisions. OBJECTIVES:To provide an overview of TECAC genetic and phenotypic holdings. MATERIALS AND METHODS:TECAC has composed by-laws describing the consortium structure and governance, codified the processes for manuscript development and data transfer, and developed guidance for the transfer of biological samples and access to data. RESULTS:TECAC has assembled a vast amount of genetic information on males with TGCT-including SNP-array data on over 13,500 cases, whole-exome sequencing data on over 4500 cases, and low-pass whole-genome sequence data on over 2700 cases. Genetic information on males without TGCT (controls) is derived from studies designed to assess risk factors for TGCT and from publicly available resources. When available, corresponding phenotypic information is collected and harmonized. Fifteen publications have resulted from genetic and phenotypic information curated by TECAC. DISCUSSION:The sharing of genetic and phenotypic data by TECAC centers to inform large studies of TGCT susceptibility has led to novel insights into the genetic architecture of this cancer, including the roles of genes involved in male germ cell development, sex determination, chromosomal segregation, and RNA transcription. These findings would not have been achievable by individual centers or smaller collaborative efforts. CONCLUSION:We invite investigators from any discipline who have access to collections of germline DNA, somatic cell DNA, or genomic information on males with TGCT to consider joining TECAC to further strengthen our efforts to reduce the global burden of TGCT.

BACKGROUND:Genomic testing will occasionally identify a highly actionable genetic variant or other finding that is not related to the reason for testing. Such incidental findings may be relevant to the patient undergoing testing or to their family members. METHODS:This guidance on managing incidental findings was developed by the British Society for Genetic Medicine to support clinicians requesting genomic tests and clinical scientists working in genomic laboratories within the National Health Service. RESULTS:Clinicians should include the possibility of incidental findings with a patient/parent(s) in discussions around genomic testing. Decisions regarding the reporting of a genetic variant unrelated to the referral reason will depend on clinical actionability, penetrance and the variant classification. Pathogenic variants may be reported if there is evidence of high penetrance and available treatment or surveillance that is likely to improve clinical outcome. Testing using large next generation sequencing gene panels and genome-wide array analysis increases the likelihood of revealing heterozygous carrier status for autosomal recessive disorders unrelated to the reason for testing. Reporting incidental heterozygous carrier status for autosomal recessive conditions is not recommended. CONCLUSION:This guidance provides a framework for the reporting of incidental findings with case examples and a cancer susceptibility gene list. Decision-making in accordance with guidelines will achieve greater consistency than case by case decisions. This guidance may be of use to healthcare professionals in other publicly funded healthcare systems with evolving genomic testing services.

With the surge in the number of variants of uncertain significance (VUS) reported in ClinVar in recent years, there is an imperative to resolve VUS at scale. Multiplexed assays of variant effect (MAVEs), which allow the functional consequence of 100s to 1000s of genetic variants to be measured in a single experiment, are emerging as a powerful source of evidence which can be used in clinical variant classification. Increasingly, multiple published MAVEs are available for the same gene, sometimes measuring different aspects of variant impact. When multiple functional roles of a gene need to be considered, combining data from multiple MAVEs may provide a more comprehensive measure of the consequence of a genetic variant, which could impact variant classifications. We curated published datasets from five MAVEs for the gene TP53, two MAVEs for LDLR and two MAVEs for PTEN. Statistical methods (principal component analysis), unsupervised learning (k-means clustering), and supervised learning (Naïve Bayes and random forest classifiers) were used to integrate multiple MAVE datasets. The utility of MAVE integration methods were assessed using standard metrics (sensitivity, specificity, etc) as well as evidence strength in a putative variant classification framework. Here, we provide guidance for combining such multiplexed functional data, incorporating a stepwise process from data curation and collection to model generation and validation. We also present a web applet that allows users to test various methods for combining score sets from multiple assays, calculate integrated functional scores for all variants, and assess whether combining data enables the application of stronger evidence for pathogenicity or benignity. In general, supervised learning methods such as random forest led to improved variant classification as compared to any individual MAVE dataset. By following the steps outlined herein with appropriate guardrails, researchers can maximize the value of MAVEs, strengthen the functional evidence for clinical variant classification, and potentially uncover novel mechanisms of pathogenicity for clinically relevant genes.

BACKGROUND:Cancer Variant Interpretation Group UK (CanVIG-UK) was established in 2017 in response to the publication of the 2015 American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) v3 guidance for the interpretation of sequence variants. Its initial purpose was to ensure consistency in the UK clinical-laboratory community implementation of ACMG/AMP v3 guidance for cancer susceptibility genes (CSGs). Still convening for monthly national meetings, the remit of CanVIG-UK now encompasses additional activities delivered under the following objectives: (1) creation of a national multidisciplinary professional network and regular forum, (2) delivery of training and education, (3) establishment of a consensus approach to the fundamentals of variant interpretation in CSGs, (4) development and ratification of gene-specific frameworks for variant interpretation for CSGs, (5) development and maintenance of an online platform to facilitate information sharing and variant interpretation within the UK clinical-laboratory community and (6) facilitation of UK contribution to international variant interpretation endeavours. METHODS:A survey of CanVIG-UK members evaluating the impact of these activities conducted in November 2025 had 163 responses, including 113 clinical scientists/trainees and 27 Clinical Genetics consultants/trainees. RESULTS:The utility of the CanVIG-UK consensus recommendations for variant interpretation in CSGs was highly rated, with 89/145 (61.4%) of survey respondents reporting using the guidance at least weekly (≥4 times/month) and 124/128 (96.9%) rating it as extremely/very useful. The usage frequency and perceived utility reported for the gene-specific guidance by survey respondents were similar. CONCLUSION:Both qualitative and quantitative survey responses clearly demonstrate the value of the CanVIG-UK activities to the clinical-diagnostic community.

BACKGROUND:Approximately 3% of patients with breast cancer have an inherited pathogenic variant in high-penetrance genes such as BRCA1, BRCA2 or PALB2. Knowledge of genetic testing result may impact surgery undertaken at the time of index breast cancer treatment. The aim of this study was to evaluate the impact of a positive high penetrance genetic test (HPGT) on surgical decision-making. METHODS:Females >18 years diagnosed with invasive breast cancer or high-grade Ductal carcinoma in situ (DCIS) without prior BRCA-gene testing were included. In patients with a germline pathogenic variant (GPV) further data on surgical decision-making were collected. RESULTS:Five hundred seventy-six patients were included. Median time from consent to result was 33 days (inter-quartile range 25-45). GPV rate was 3.6% (21/576): 11 BRCA1 (1.9%), 6 BRCA2 (1%), 4 PALB2 (0.7%). Five (23.8%) of 21 patients with GPV would not have been eligible for HPGT on the UK National Health Service R208 pathway. Four hundred eighty (83.3%) of the 576 patients underwent primary breast cancer surgery; 121 (25.2%) of 480 patients received results pre-operatively, 359 (74.8%) post-operatively. Pre-operative GPV knowledge significantly influenced the initial surgical procedure undertaken (P = .002). Uptake of subsequent risk-reducing surgery was higher with a preoperative result (100% vs. 71.4%), although this difference was not statistically significant (P = .24). CONCLUSIONS:Early timing of positive HPGT results significantly influences surgical decision-making and increases pre-operative uptake of bilateral risk-reducing mastectomy. Expanded HPGT access in this study identified 24% additional patients with GPV who would not have met current UK testing criteria.

In the North Thames Mainstreaming of Breast Cancer Genetic Testing (NT-MBGT) programme, we piloted testing for breast cancer susceptibility genes (BCSGs) in unselected breast cancer (BC) patients, deploying a clinician-light ‘BRCA-DIRECT’ mainstreaming pathway; this included home saliva-testing and consent with postal return, written and digital materials, with full access to a Genetic Counsellor Telephone helpline. Across 14 National Health Service (NHS) breast oncology units, we successfully tested 3515 newly-diagnosed BC patients with high levels of patient and breast healthcare professional (HCP) satisfaction and genetics HCPs reporting decreases in service referrals. The pick-up rate of gPVs was 4.7% (166 germline Pathogenic Variants (gPVs) across seven BCSGs). Examining application of current NHS eligibility criteria to the unselected cohort, testing would have been offered to 20.6% of patients with identification of 49.2% of gPVs in high penetrance (HP)-BCSGs (BRCA1/BRCA2/PALB2) and 18.2% of gPVs in intermediate penetrance-BCSGs (CHEK2/ATM/RAD51C/RAD51D). Designing ‘Ultra-simple’ eligibility criteria suitable for mainstreaming, detection (sensitivity) could be improved to 81.1% and 70.4% respectively, whilst increasing testing to 49.7% of BC cases. Evidence from the NT-MBGT programme demonstrates that expanding BCSG-testing via a clinician-light pathway is acceptable and feasible, without increasing the burden on limited breast and genetics workforce, and has high satisfaction.

Background:Large-scale functional assays, including multiplex assays of variant effect, have substantial potential to resolve variants of uncertain significance (VUS), particularly for rare missense variants where clinical and population evidence are limited. The ClinGen assay-level clinical validation framework described by Brnich et al provided baseline guidance for the use of functional data for variant classification. However, clear consensus regarding construction of variant 'truthsets' by which to clinically validate functional data remains lacking. Methods:CanVIG-UK developed consensus recommendations for truthset construction through an iterative national consultation process involving the CanVIG Steering Advisory Group (CStAG), wider CanVIG-UK membership, and engagement with international functional genomics experts. Consultation was based on previous analyses of 2,120 truthset constructions examining the impact of truthset composition on evidence point allocation within the ClinGen assay-level clinical validation framework. Results:Across several consultations, CanVIG-UK established nine guiding principles and seven best-practice recommendations for assay-level clinical validation, using the assumed context of an assay for a cancer susceptibility gene where loss-of-function is the mechanism of pathogenicity. The principal recommendation stipulates, where assays are intended for use in interpretation of largely missense variants, the truthset used to validate should comprise only missense variants. Rather than mixtures of different variant types which may serve to over-estimate assay performance. Additional recommendations support option for relaxation of truthset stringency to improve power, augmentation of benign missense truthsets with systematically derived 'proxy-clinical' benign variants, independent clinical validation separate from assayist-defined validation, and careful evaluation of missense score distributions against that of protein-truncating and synonymous variants. Guidance is also provided for scenarios with limited pathogenic truthset availability and for assays reporting multiple deleterious zones or readouts. Conclusions:The CanVIG-UK principles and recommendations for truthset construction upon the ClinGen assay-level clinical validation framework, while aiming to form a baseline for future discussion regarding other functional and disease contexts and helping to address the gap between publication of new data and routine clinical implementation.

Purpose:Germline deletions affecting the Y-chromosomal gr/gr region were reported in 2005 as associated with susceptibility to testicular germ cell tumor (TGCT), a highly heritable tumor type that is the most common cancer type affecting adult men under the age of 45. Attempts to replicate this association have been equivocal, primarily due to limited power. Methods:Here, we compare and validate two computational approaches to gr/gr deletion calling in high-, low- and ultra-low-coverage whole genome sequencing data, applying these to two datasets from UK Biobank and the TECAC consortium. We generate dataset-specific effect size estimates for the gr/gr deletion-TGCT association using Firth's bias-reduced logistic regression across a total of 198,306 men of European-like ancestry (2231 with and 196,075 without TGCT). Results:Upon random-effects meta-analysis of estimated effect sizes in the two datasets, we found no significant association between gr/gr deletion status and TGCT risk (combined odds ratio=1.24, 95% CI=0.74-2.07, p=0.42), nor upon stratification of seminoma and non-seminoma/mixed histological subtypes. Conclusion:Our analysis suggests gr/gr deletion status alone is likely not predictive of TGCT risk in population-scale analyses of European-like individuals; however, the importance of other proposed determinants of gr/gr deletion impact, including Y-haplogroups and semen phenotype, remains unexplored at scale.

ABSTRACT Background Lynch syndrome (LS) is a cancer susceptibility syndrome caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. Due to increased risk of colorectal cancer (CRC), enhanced colonoscopic surveillance is recommended for heterozygote MMR-carriers. Objective Using a registry of English LS patients linked to digital National Health Service records, we aimed to assess adherence of MMR-carriers to national surveillance guidelines, and to determine the impact of surveillance on CRC incidence and mortality. Design We described the frequency of colonoscopies in 4,732 MMR-carriers and used logistic regression to determine predictors of surveillance adherence. For MMR-carriers with a record of surveillance and those without, we: estimated age-specific annual CRC incidence rates (AS-AIRs) and cumulative lifetime risks, assessed for stage-shift by comparing CRC stage distributions and stage-specific AS-AIRs, and estimated risks of death from CRC and any cause using Kaplan-Meier methods and Cox Proportional Hazards regression. Results Surveillance at a mean interval of ≤ 3 years (n=3028) was associated with a decrease in CRC-specific and all-cause mortality, without an associated change in total CRC incidence, even after multivariate adjustment. No strong evidence of stage-shift was observed. Colonoscopic surveillance at a mean interval of ≤ 2 years (n=1569) was associated with an increase in total CRC incidence. Incidence of early-stage cancers was also higher, with no corresponding decrease in late-stage cancers, which may reflect the short follow-up period or the impact of overdiagnosis. Conclusion The observed reduction in all-cause mortality amongst regularly-surveilled MMR-carriers may indicate an impact of surveillance on CRC-specific mortality, though in the context of a non-randomised study likely reflects the influence of selection bias. KEY MESSAGES OF ARTICLE What is already known on this topic Regular surveillance colonoscopy is recommended in Lynch syndrome, though evidence to support this remains mixed. We searched PubMed for articles published from inception to 01/05/2024 using the terms “Lynch syndrome”, “HNPCC”, “colonoscopy”, “sigmoidoscopy”, “surveillance”, and “screening”. We found one controlled trial and several small analytical studies dating from the early 2000s which compared surveilled and non-surveilled populations and found surveillance to be associated with reduced colorectal cancer (CRC) incidence and improved survival. More recent longitudinal observational studies, most without comparator groups, found a high incidence of CRC in LS populations despite being resident in countries where surveillance was recommended. A small number of studies directly assessed time since last colonoscopy against CRC incidence and stage with mixed findings. Finally, cross-sectional comparisons between countries of CRC incidence rates and surveillance interval recommendations found no relationship between the two 1,2 . What this study adds Here, we conduct an observational cohort study on a large national cohort of MMR germline pathogenic variant (GPV) carriers (MMR-carriers) in England (n=4,732), comparing CRC incidence and mortality in individuals with a record of regular surveillance to those without. Through linkage of the English National Lynch Syndrome Registry to Hospital Episodes Statistics data, we are uniquely able to study a comprehensive national population of MMR-carriers and identify the dates on which colonoscopies were undertaken over time, allowing assessment of adherence to national surveillance guidelines and the impact this has on CRC outcomes. Notably, receipt of regular colonoscopy was strongly associated with deprivation as well as ethnicity. The results show that regular surveillance at an average interval of 3 years (or less) is not associated with a reduction in CRC incidence when compared to less frequent surveillance, but an apparent decrease in both CRC-specific and overall mortality is observed, even after adjustment for confounding variables. Conversely, regular surveillance at an average interval of 2 years (or less) is associated with an increase in CRC incidence when compared to less frequent surveillance, which may suggest increased diagnosis of early-stage cancers or, due to the absence of a reduction in late-stage cancers, overdiagnosis. The observed impact of surveillance on overall mortality may demonstrate the impact of surveillance on CRC-specific mortality, or, in the context of an observational (non-randomised) study, indicate that the results are subject to selection bias. How this study might affect research, practice, or policy Evidence for the benefit of surveillance colonoscopy remains mixed. Whilst polypectomy would be anticipated to prevent CRC development (thus reducing CRC incidence), several studies have observed increased frequency of CRCs in MMR-carriers undergoing frequent surveillance colonoscopy, which may reflect overdiagnosis. The selection bias inherent to observational studies of surveillance renders mortality outcomes challenging to interpret. Randomised controlled trials of colonoscopic surveillance in MMR-carriers are required for effectiveness of this intervention to be accurately assessed. Given ethical and feasibility challenges, randomised controlled trials might be complemented by quasi-experimental designs using advanced observational methods for assessing effectiveness.

Interpretation of genetic variants is most accurate when gene- and disease-specific considerations are considered. The 2015 ACMG/AMP guidelines form the basis for the application of variant interpretation criteria for Mendelian disorders. The Hereditary Breast, Ovarian, and Pancreatic Cancer Variant Curation Expert Panel (HBOP VCEP) has undertaken the process for creating gene- and disease-specific specifications for the interpretation of PALB2 germline sequence variants. The HBOP VCEP is comprised of experts in the fields of clinical and molecular genetics, epidemiology, functional assays, and variant interpretation. The group met regularly to consider each of the codes from the 2015 ACMG/AMP guidelines to determine their relevance for PALB2. After criteria were created using database analysis, literature review, and expert opinion, they were vetted against a diverse set of pilot variants and ultimately finalized. The HBOP VCEP advised against using 13 codes, limited the use of six codes, and tailored nine codes to create the final PALB2 variant interpretation guidelines. Among the 39 pilot variants, 37 were in ClinVar, and using the new specifications concordant classifications resulted for 31 of the variants (84%). Of the 14 variants of uncertain significance/conflicting variants in ClinVar, four were classified by the VCEP, likely due to code combination modifications and refined population frequency cutoffs. The PALB2-specific guidelines put forward by the HBOP VCEP represent a conservative approach to classifying variants in PALB2 and lead to improved classifications relative to current ClinVar entries. Adoption of these specifications will help to harmonize classifications deposited in the public domain.

Objectives To investigate the association between bilateral salpingo-oophorectomy (BSO) and long-term health outcomes in women with a personal history of breast cancer.Methods and analysis We used data on women diagnosed with invasive breast cancer between 1995 and 2019 from the National Cancer Registration Dataset (NCRD) in England. The data were linked to the Hospital Episode Statistics-Admitted Patient Care dataset to identify BSO delivery. Long-term health outcomes were selected from both datasets. Multivariable Cox regression was used to examine the associations, with BSO modelled as a time-dependent covariate. The associations were investigated separately by age at BSO.Results We identified 568 883 women, 23 401 of whom had BSO after the breast cancer diagnosis. There was an increased risk of total cardiovascular diseases with an HR of 1.10 (95% CI 1.04 to 1.16) in women who had BSO<55 years and 1.07 (95% CI 1.01 to 1.13) for women who had BSO≥55 years. There was an increased risk of ischaemic heart diseases, but there was no association with cerebrovascular diseases. BSO at any age was associated with an increased risk of depression (HR 1.20, 95% CI 1.12 to 1.28) and increased risk of second non-breast cancer in older women (HR 1.21, 95%CI 1.08 to 1.35). BSO in older women was associated with reduced risk of all-cause mortality (HR 0.92, 95% CI 0.87 to 096), but not in women who had BSO<55 years.Conclusion In women with a personal history of breast cancer, BSO before and after the age of 55 years is associated with an increased risk of long-term outcomes. BSO after 55 years is associated with reduced all-cause mortality. Family history or genetic predisposition may confound these associations.