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Purpose: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene (CSG) as though having equivalent penetrance, despite increasing evidence of inter-variant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants where reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance (VUS). We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network., Methods: A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group (CStAG) working group., Results: CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants where (A) Active evidence suggests a reduced penetrance effect size (e.g. from case-control or segregation data) (B) Reduced penetrance effect is inferred from weaker/potentially-inconsistent observed data., Conclusions: CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, whilst developed for CSGs, are potentially applicable to other clinical contexts., (Copyright © 2024. Published by Elsevier Inc.)

Background: The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity., Methods: We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non-association (eg, OR≤1)., Results: PS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation., Conclusion: PS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objective: To determine the frequency of germline and somatic pathogenic BRCA1 and BRCA2 variants in patients with high-grade serous ovarian cancer tested by next-generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing., Design: National retrospective audit., Setting: The All Wales Medical Genomics Service (AWMGS)., Population: Patients with high-grade serous ovarian/fallopian tube/peritoneal cancer referred by oncologists to the AWMGS between February 2015 and February 2021 for germline and/or tumour testing of the BRCA1 and BRCA2 genes by NGS., Methods: Analysis of NGS data from germline and/or tumour testing., Main Outcome Measures: Frequency of BRCA1 and BRCA2 pathogenic variants., Results: The overall observed germline/somatic pathogenic variant detection rate was 11.6% in the 844 patients included in this study, with a 9.2% (73/791) germline pathogenic variant detection rate. Parallel tumour and germline testing was carried out for 169 patients and the overall pathogenic variant detection rate for this cohort was 14.8%, with 6.5% (11/169) shown to have a somatic pathogenic variant. Two BRCA1 dosage variants were found during germline screens, representing 2.0% (2/98) of patients with a pathogenic variant that would have been missed through tumour testing alone., Conclusions: Parallel germline and tumour BRCA1 and BRCA2 testing maximises the detection of pathogenic variants in patients with high-grade serous ovarian cancer., Tweetable Abstract: Parallel germline and tumour testing maximises BRCA pathogenic variant detection in ovarian cancer., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

The Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE) family are a group of molecules that form a key link between GTPases and the actin cytoskeleton. The role of WASP/WAVE family proteins in the control of actin polymerization through activation of the actin-related protein 2/3 complex is critical in the formation of the actin-based membrane protrusions seen in cell migration and invasion. For this reason, the activity of the WASP/WAVE family in cancer cell invasion and migration has been of great interest in recent years. Many reports have highlighted the potential of targeting the WASP/WAVE family as a therapy for the prevention of cancer progression, in particular breast cancer. This review focuses on the role of the WASP/WAVE family in breast cancer cell invasion and migration and how this relates to the molecular mechanisms of WASP/WAVE activity, their exact contributions to the stages of cancer progression, and how this can lead to the development of anticancer drugs that target the WASP/WAVE family and related pathways.