PALB2 (Partner and localizer of BRCA2)

The INHERITY LC study identified a PGV prevalence of 10.3% in a selected NSCLC cohort, with most variants affecting genes involved in the DNA damage repair (DDR) pathway. The application of specific selection criteria may enhance the yield of germline testing in this setting. Larger confirmatory studies are warranted to demonstrate that germline testing and genetic counseling for NSCLC may have implications for prevention, early detection, and treatment.

By contrast, for moderately penetrant genes, standard PGT-M would fail to select the lowest risk embryo approximately 5% of the time due to elevated PRS. This complex interplay suggests that caution should be exercised when considering preimplantation genetic testing involving exclusively monogenic variants of moderate penetrance or polygenic scores.

P=N/A, N=332, Completed, University Health Network, Toronto | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Aug 2025 | Trial primary completion date: Dec 2024 --> Aug 2025

© 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

A 54-year-old woman was diagnosed with stage IIIB HER2-positive invasive breast cancer in 2017 and treated with neoadjuvant chemotherapy (TAC), modified radical mastectomy, radiotherapy, trastuzumab, and toremifene...It suggests that VUS in genes involved in cellular stress and metabolic pathways, particularly in combination with TP53 mutations, may contribute to the development of multiple primary malignancies. Furthermore, it underscores the importance of vigilant, phenotype-driven long-term surveillance in such patients, regardless of germline testing results.

Promising results have led to the approval of several PARPi agents as monotherapy or in combination with ARPIs in selected or unselected patients when chemotherapy is not clinically indicated. However, some questions remain regarding patient selection and treatment sequencing.

Integration of PV status, PRS, and family history enables more refined PCa risk estimates. The wide range of PCa risk observed among men of African ancestry in our study supports future prospective studies in the development of risk-stratified cancer screening programs to identify high-risk individuals who may benefit from screening at an earlier age.

In this clinical opinion we describe that while RRS+DO has been associated with improved menopause-related quality of life and reduced cancer worry, its efficacy in cancer risk reduction has not been established. We explain the importance of offering RRS+DO within clinical trials whenever possible.

A similar permutation approach revealed significant differences in the magnitude of breast cancer risk according to the BRCA1 and BRCA2 allele severity score in heterozygotes. Our findings indicate the potential to redefine FA ORPHA:84 HPO terms and to use an allele severity scoring approach to predict cancer risk in individuals with bi-allelic or heterozygous BRCA1 or BRCA2 variants.

The consensus meeting broadly supported recontact and follow-up for most individuals with a GPV in a CSG. The consensus achieved by the multidisciplinary and expert group of healthcare professionals gives clear guidance on the long-term management of this patient cohort at increased lifetime risk of cancer and highlights the additional resources that would be required to effectively deliver this.

Baseline low ctDNA levels predict response to targeted therapy, potentially suggesting shared mechanisms between high ctDNA release and resistance to therapy. Both baseline ctDNA levels and on-treatment dynamics are a promising surrogate endpoint for drug development, with clearance of ctDNA being a robust cross-therapy surrogate for outcome.

We also identified nine variants with a severe impact on BRCA2 binding and HR repair. We propose that these variants, which consistently show loss of function in different functional assays, represent pathogenic cancer predisposing variants.