ArticleHuman mutation2008
Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.
Article in Human mutation, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers.
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Who cites it
131 citing papers in PubMed.
- Reclassification ofBiomolecules & biomedicine · 2026Article
- Cancer-associated TRF1 mutations alter PARP1 interaction dynamics: an in silico study.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- Molecular Mechanisms of CLCN5 Missense Mutations in Dent Disease Type 1: A Comprehensive Computational Analysis and Clinical Correlations in a Chinese Cohort.Journal of cellular and molecular medicine · 2026Article
- Enhanced computational strategies for categorizing HER2 kinase domain variants of uncertain significance through structural and functional analysis.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Characteristics predicting reduced penetrance variants in the high-risk cancer predisposition gene TP53.HGG advances · 2025Article
- When two plus four does not equal six: Combining computational and functional evidence to classify BRCA1 key domain missense substitutions.American journal of human genetics · 2025Article
- A pro-angiogenic and hypoxic zebrafish model as a novel platform for anti-angiogenic drug testing.Biology open · 2025Article
- Cadherin 1 germline mutation co-occurs with medullary thyroid cancer and choroid plexus papilloma: A case report and review of literature.Surgical neurology international · 2025Article
- Article
- Safety of the Breast Cancer Adjuvant Radiotherapy in Ataxia-Telangiectasia Mutated Variant Carriers.Cancers · 2024Article
- A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis.Metabolic brain disease · 2024Article
- MMPatho: Leveraging Multilevel Consensus and Evolutionary Information for Enhanced Missense Mutation Pathogenic Prediction.Journal of chemical information and modeling · 2023Article
- Saturation genome editing of 11 codons and exon 13 of BRCA2 coupled with chemotherapeutic drug response accurately determines pathogenicity of variants.PLoS genetics · 2023Article
- The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition.Cancer science · 2023Article
- Overview of the Genetic Causes of Hereditary Breast and Ovarian Cancer Syndrome in a Large French Patient Cohort.Cancers · 2023Article
- Functional Analyses of Rare Germline MissenseGenes · 2023Article
- Computational analysis of the functional and structural impact of the most deleterious missense mutations in the human Protein C.PloS one · 2023Article
- ASCARIS: Positional feature annotation and protein structure-based representation of single amino acid variations.Computational and structural biotechnology journal · 2023Article
- Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.Human mutation · 2022Article
- An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance.NPJ genomic medicine · 2022Article
71 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors.
Funding
Abstract
Many individually rare missense substitutions are encountered during deep resequencing of candidate susceptibility genes and clinical mutation screening of known susceptibility genes. BRCA1 and BRCA2 are among the most resequenced of all genes, and clinical mutation screening of these genes provides an extensive data set for analysis of rare missense substitutions. Align-GVGD is a mathematically simple missense substitution analysis algorithm, based on the Grantham difference, which has already contributed to classification of missense substitutions in BRCA1, BRCA2, and CHEK2. However, the distribution of genetic risk as a function of Align-GVGD's output variables Grantham variation (GV) and Grantham deviation (GD) has not been well characterized. Here, we used data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests plus two risk estimates, one approximating the odds ratio and the other reflecting strength of selection, to display the distribution of risk in the GV-GD plane as a series of surfaces. We abstracted contours from the surfaces and used the contours to define a sequence of missense substitution grades ordered from greatest risk to least risk. The grades were validated internally using a third, personal and family history-based, measure of risk. The Align-GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiology problem of analyzing rare missense substitutions observed during case-control mutation screening studies of candidate susceptibility genes.
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