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Introduction: Approximately 10% of breast cancer (BC) cases result from hereditary causes. Genetic testing has been widely implemented in BC care to determine hereditary cancer syndromes and personalized medicine. Thus, identification of individuals carrying germline pathogenic variants could be useful to provide appropriate prophylactic or screening measures for each BC subtype, however, there are few formal recommendations for genetic testing in this sense so far. In this study, we assessed rare germline variants in a specific group of genes in order to determine the association with human epidermal growth factor 2 enriched (HER2+) BC phenotype through a systematic review and meta-analysis comparing subtypes overexpressing HER2 with other clinically recognized subtypes of BC. This review was registered with PROSPERO (ID: CRD42023447571)., Methods: We conducted an online literature search in PubMed (MEDLINE), Scopus, and EMBASE databases. We included original studies that investigated germline variants in HER2+ BC patients and selected the studies that reported only rare and/or pathogenic germline variants. We assessed the risk of bias and quality of the studies using the Joanna Briggs Institute Critical Appraisal checklists and the Modified Newcastle-Ottawa Scale for Genetic Studies, respectively. Considering hormone receptor and HER2 expression status, we compared gene-based risks initially in HR-HER2-, HR+HER2-, HR+HER2+, and HR-HER2+ groups, conducting separate meta-analyses using the random effects model for each comparison, and within them for each gene., Results: Of the total 36 studies describing germline variants, 11 studies provided information on the prevalence of variants in the different clinically relevant BC subtypes and allowed comparisons. Germline variants within eight genes showed significant differences when meta-analyzed between the BC groups: BRCA1 , BRCA2 , TP53 , ATM , CHEK2 , PALB2 , RAD51C , and BARD1 . Notably, TP53 , ATM , and CHEK2 germline variants were identified as predisposing factors for HER2+ subtypes, whereas BRCA1 , BRCA2 , PALB2 , RAD51C , and BARD1 germline variants were associated with a predisposition to low HER2 expression. Main concerns about bias and quality assessment were the lack of confounding factors control; and comparability or outcome assessment, respectively., Discussion: Our findings underscore the connection between germline variants and differential expression of the HER2 protein and BC subtypes., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023447571., Competing Interests: CB receives speaker honorarium from Novartis, Bayer and Astrazeneca and research honorarium from Novartis. GaD receives speaker honorarium from Merck, Pfizer, GSK, Roche, Novartis, Bayer and Astrazeneca. DD provided consultancy services to Roche, Novartis, AstraZeneca, Lilly, Libbs, Pfizer, Dr. Reddy’s, Teva, United Medical, Daiichi Sankyo, Gilead. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 de Baumont, Cadore, Pedrotti, Curzel, Schuch, Bessel, Bordignon, Rosa, Macedo and Rosa.)

COVID-19 pandemic represented a worldwide major challenge in different areas, and efforts undertaken by the scientific community led to the understanding of some of the genetic determinants that influence the different COVID-19 outcomes. In this paper, we review the studies about the role of human genetics in COVID-19 severity and how Brazilian studies also contributed to those findings. Rare variants in genes related to Inborn Errors of Immunity (IEI) in the type I interferons pathway, and its phenocopies, have been described as being causative of severe outcomes. IEI and its phenocopies are present in Brazil, not only in COVID-19 patients, but also in autoimmune conditions and severe reactions to yellow fever vaccine. In addition, studies focusing on common variants and GWAS studies encompassing worldwide patients have found several loci associated with COVID-19 severity. A GWAS study including only Brazilian COVID-19 patients identified a new locus 1q32.1 associated with COVID-19 severity. Thus, more comprehensive studies considering the Brazilian genomic diversity should be performed, since they can help to reveal not only what are the genetic determinants that contribute to the different outcomes for COVID-19 in the Brazilian population, but in the understanding of human genetics in different health conditions.