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Last Posted: Aug 04, 2022
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A digital pathway for genetic testing in UK NHS patients with cancer: BRCA-DIRECT randomised study internal pilot.
Torr Bethany et al. Journal of medical genetics 2022 7

We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomized comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway). Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety.

Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in patients with triple-negative breast and ovarian carcinomas
F Menghi et al, Sci Trans Med, July 6, 2022

The authors examined the differences in response to platinum therapy of patients with TNBC and OvCa who had BRCA loss or genetic alterations as compared to promotor methylation of BRCA. They saw that both patients and mice with promotor methylation were able to adaptively lose methylation, gain BRCA1 expression, and acquire resistance to platinum therapy. These findings have broad implications in using BRCA alteration status to better predict patient.

How does re-classification of variants of unknown significance (VUS) impact the management of patients at risk for hereditary breast cancer?
Kwong Ava et al. BMC medical genomics 2022 6 (1) 122

The popularity of multigene testing increases the probability of identifying variants of uncertain significance (VUS). While accurate variant interpretation enables clinicians to be better informed of the genetic risk of their patients, currently, there is a lack of consensus management guidelines for clinicians on VUS. A review of archival variants from BRCA1 and BRCA2 genetic testing changed the management for 31.8% of the families due to increased or reduced risk. We encourage regular updates of variant databases, reference to normal population and collaboration between research laboratories on functional studies to define the clinical significances of VUS better.

An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance
ES Iverson et al, NPJ Genomic Medicine, June 3, 2022

We have developed functional assays and a statistical model called VarCall for classifying BRCA1 and BRCA2 VUS. Here we describe a multifactorial extension of VarCall, called VarCall XT, that allows for co–analysis of multiple forms of genetic evidence. We evaluated the accuracy of models defined by the combinations of functional, in silico protein predictors, and family data for VUS classification. VarCall XT classified variants of known pathogenicity status with high sensitivity and specificity, with the functional assays contributing the greatest predictive power

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