Missense Mutations in Cancer Predisposing Genes: Can We Make Sense of Them?

Cliff J Meldrum,Rodney J Scott

doi:10.1186/1897-4287-3-3-123

Abstract

In the analysis of genes associated with predispositions to malignancy the causative status of mutations can be made relatively easily where it is obvious that there is a clear disruption in the coding sequence of the gene. Difficulties arise, however, if missense mutations are identified, as these are not easily categorised into genetic variants that are not associated with disease risk or into clearly causative changes that impart a significant risk of disease.As more individuals are subject to DNA sequence analysis for the identification of causative changes in genes associated with cancer predisposition, an increasing number of missense mutations are being identified. Causative status assignment to missense mutations continues to be problematic especially where no functional assessment of the alteration can be made. As more information is gathered on missense mutations our predictive ability to assign significance will improve.In this report we review, in broad terms, what measures can be undertaken to categorise missense mutations into those that are clearly causative, probably causative and most likely not causative.

Highlights

There are many facets that need to be considered when determining whether a missense mutation is causative or just a common polymorphism that has no impact on the functional activity of the gene in question
The definition of a missense mutation is ‘a single base pair substitution that results in the translation of a different amino acid at that position’ [1]
This differentiates missense changes from silent polymorphisms where there is no apparent change in the protein product of the gene

Summary

Introduction

There are many facets that need to be considered when determining whether a missense mutation is causative or just a common polymorphism that has no impact on the functional activity of the gene in question. The definition of a missense mutation is ‘a single base pair substitution that results in the translation of a different amino acid at that position’ [1]. This differentiates missense changes from silent polymorphisms where there is no apparent change in the protein product of the gene. In determining the effect of missense changes a number of avenues of investigation can be followed. These include the association of missense changes with disease (segregation analysis), the evolutionary

Breast Cancer

Can missense mutations be classified in the absence of functional studies?

Evolutionary conservation