Background: BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast-ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk.
Objective: To investigate a panel of missense variants.
Methods And Results: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396-1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated.
Conclusions: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735988 | PMC |
| http://dx.doi.org/10.1136/jmg.2004.024711 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Missense variants at the p.Arg225 residue in ARHGEF40 identified in individuals with multiple congenital anomalies and developmental delay.
HGG Adv
January 2025
GeneDx LLC, Gaithersburg, Maryland, 20877.
The ARHGEF40 gene, also known as SOLO, encodes a RhoA-targeting guanine nucleotide exchange factor (GEF) and is currently considered a candidate gene with a potential relationship to disease. Our laboratory has confirmed variants at position p.Arg225 of the ARHGEF40 protein in multiple unrelated individuals with a phenotype including dysmorphic features, congenital anomalies and neurodevelopmental abnormalities.
View Article and Find Full Text PDFGenetic variations underlying aminoglycoside resistance in antibiotic-induced Mycobacterium intracellulare mutants.
Infect Genet Evol
January 2025
Department of Microbiology, College of Medicine, Gyeongsang National University, Jinju, Republic of Korea; Department of Convergence of Medical Science, Gyeongsang National University, Jinju, Republic of Korea. Electronic address:
Mycobacterium avium complex (MAC) is an emerging pathogen leading to public health concerns in developing and developed countries, particularly among immunocompromised individuals and patients with structural lung diseases. Current clinical guidelines recommend combination antibiotic therapy for treating MAC pulmonary disease (MAC-PD). However, the rising prevalence of antibiotic resistance poses significant challenges, including treatment failure and clinical recurrence.
View Article and Find Full Text PDFMulti-modal investigation reveals pathogenic features of diverse DDX3X missense mutations.
PLoS Genet
January 2025
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
De novo mutations in the RNA binding protein DDX3X cause neurodevelopmental disorders including DDX3X syndrome and autism spectrum disorder. Amongst ~200 mutations identified to date, half are missense. While DDX3X loss of function is known to impair neural cell fate, how the landscape of missense mutations impacts neurodevelopment is almost entirely unknown.
View Article and Find Full Text PDFFunctional validation of a novel STAT3 'variant of unknown significance' identifies a new case of STAT3 GOF Syndrome and reveals broad immune cell defects.
Clin Exp Immunol
January 2025
Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Introduction: STAT3 orchestrates crucial immune responses through its pleiotropic functions as a transcription factor. Patients with germline monoallelic dominant negative or hypermorphic STAT3 variants, who present with immunodeficiency and/or immune dysregulation, have revealed the importance of balanced STAT3 signaling in lymphocyte differentiation and function, and immune homeostasis. Here, we report a novel missense variant of unknown significance in the DNA binding domain of STAT3 in a patient who experienced hypogammaglobulinemia, lymphadenopathy, hepatosplenomegaly, immune thrombocytopenia, eczema and enteropathy over a 35-year period.
View Article and Find Full Text PDFClinical Features and Genetic Characteristics of XLID Patients With KDM5C Gene Mutations: Insights on Phenotype-Genotype Correlations From 175 Previous Cases and Identification of a Novel Variant.
Mol Genet Genomic Med
January 2025
Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Background: X-linked intellectual disability (XLID) is a genetically heterogeneous disorder that results in cognitive impairment and developmental delays. Mutations in the KDM5C gene have been identified as a causative factor in XLID. This study aimed to identify novel variants associated with XLID and to investigate the clinical and genetic characteristics of XLID patients with mutations in the KDM5C gene.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!