'A variant of uncertain significance' and the proliferation of human disease gene databases

The rapid accumulation of mutation data has led to the creation of nearly 300 locus-specific mutation databases. These sites may contain a few dozen to almost 20,000 mutations for a given gene. Many of the mutations are uncharacterised and have no known effects on the gene product, the 'variant of uncertain significance'. Here, the statistics of mutation distribution are examined for six different gene databases: BRCA1 and BRCA2, haemoglobin-beta (HBB), HPRT1, CFTR and TP53. The percentage of all possible point mutations for a protein (the mutation space) is calculated for each gene and the question 'How much mutation data is enough?' is raised.

• Publication year

  2005

• Venue

  Human Genomics

• Publication date

  2005-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/1479-7364-2-1-70PMID 15814069PMCID 3525115
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation

  2004influential reference
• The Pfam protein families database

  2004cited by this paper
• Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2.

  2004cited by this paper
• Structural and functional analysis of mutations at the human hypoxanthine phosphoribosyl transferase (HPRT1) locus

  2004cited by this paper
• Online Mendelian Inheritance in Man 'OMIM'.

  2003cited by this paper
• Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

  2003cited by this paper
• Of mice and (wo)men: genotype-phenotype correlations in BRCA1.

  2003cited by this paper
• HbVar: A relational database of human hemoglobin variants and thalassemia mutations at the globin gene server

  2002cited by this paper
• The IARC TP53 database: New online mutation analysis and recommendations to users

  2002cited by this paper
• The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases.

  2000cited by this paper
• BRCA1 and BRCA2 gene mutation analysis: visit to the Breast Cancer Information Core (BIC).

  1999cited by this paper
• Databases and software for the analysis of mutations in the human p53 gene, human hprt gene and both the lacI and lacZ gene in transgenic rodents

  1998cited by this paper
• Human Gene Mutation Database

  1996cited by this paper
• Mutations and Polymorphisms in the familial early‐onset breast cancer (BRCA1) gene

  1996cited by this paper

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  2020cites this paper
• Variants of uncertain significance in breast cancer-related genes: real-world implications for a clinical conundrum. Part one: clinical genetics recommendations.

  2011cites this paper
• Scientific & recent submissions

  2011cites this paper
• The counsellees' view of an unclassified variant in BRCA1/2: recall, interpretation, and impact on life

  2008cites this paper
• Locus-specific mutation databases: pitfalls and good practice based on the p53 experience

  2006cites this paper