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Establishing the pathogenic nature of variants in ATM, a gene associated with breast cancer and other hereditary cancers, is crucial for providing patients with adequate care. Unfortunately, achieving good variant classification is still difficult. To address this challenge, we extended the range of in silico tools with a series of graphical tools devised for the analysis of computational evidence by health care professionals. We propose a family of fast and easy-to-use graphical representations in which the impact of a variant is considered relative to other pathogenic and benign variants. To illustrate their value, the representations are applied to three problems in variant interpretation. The assessment of computational pathogenicity predictions showed that the graphics provide an intuitive view of prediction reliability, complementing and extending conventional numerical reliability indexes. When applied to variant of unknown significance populations, the representations shed light on the nature of these variants and can be used to prioritize variants of unknown significance for further studies. In a third application, the graphics were used to compare the two versions of the ATM-adapted American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, obtaining valuable information on their relative virtues and weaknesses. Finally, a server [ATMision (ATM missense in silico interpretation online)] was generated for users to apply these representations in their variant interpretation problems, to check the ATM-adapted guidelines' criteria for computational evidence on their variant(s) and access different sources of information., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity., Patients and Methods: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi., Results: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor., Conclusion: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

It is not known if the behaviour of hereditary breast cancer (HBC) differs from that of sporadic breast cancer (BC). The aim of the present study was to analyze clinical-pathological characteristics in patients with BRCA1/2-mutation associated to BC. These data could be useful in the management of HBC. This study includes 17 patients with BC in whom a germ-line BRCA1/2-mutation was diagnosed. The patients were from 10 different families, and four patients had no family history of BC or ovarian cancer (OC). The study of mutations was with the protein truncation test (exon 11 for BRCA1, exons 10 and 11 for BRCA2) and sequencing (the rest of exons). At diagnosis the mean age was 37 years (28-54). Only 3/17 patients presented with involvement of axillary nodes; no patient was diagnosed with metastatic disease. All cases were infiltrating ductal carcinoma; two of them were medullary carcinoma. Histological grade was available in 13/17 cases, with grade III being the most frequent (12/13). Hormonal receptors were negative in 8/10 patients. The mean follow-up was 129 months (23-223). There were three local recurrences at 17, 108 and 151 months; and two distant relapses at 15 months (complete remission) and 92 months. There were three diagnosed contralateral BC. Hereditary breast cancer has malignant pathological features, but the clinical behaviour may be less aggressive than sporadic breast cancer in the same age group.

Background: Mutations in the BRCA2 gene account for the majority of the families with male and female breast cancer cases, and a number of BRCA2 mutations have been reported in males with breast cancer. The aim of this study was to characterise BRCA2 germ-line mutations in Spanish male breast cancer patients., Patients and Methods: We screened DNA from 11 affected men and 6 women with breast cancer (BC) who had an affected male relative (father or brother). Exons 2-9 and 12-27 were screened by SSCP, and exons 10 and 11 were screened by PTT. PCR products with a variant band were sequenced., Results: Three BRCA2 frameshift mutations were identified (17.6%): the 3374delA in codon 1049 (exon 11), 6857delAA in codon 2010 (exon 11), and 9254delATCAT in codon 3009 (exon 23). These mutations were present in patients with affected first-degree relatives (3 of 9, 33%). The proportion of male patients with a family history of BC in at least one first-degree relative was 53%., Conclusions: There is an association between BRCA2 mutations and male breast cancer, especially in those with a family history of BC. The high prevalence of BRCA2 mutations among males should be considered when estimating risk for female relatives. All new male cases of BC should be regarded as being possibly inherited and should be fully investigated.