Growing Recognition of the Role for Rare Missense Substitutions in Breast Cancer Susceptibility

Abstract

Most cancer susceptibility genes function as tumor suppressors; accordingly, the focus of mutation screening in breast cancer families has been to identify protein-truncating mutations. However, it is now clear that, for some breast cancer susceptibility genes, a significant proportion of the burden of disease comes from rare missense substitutions. Among genes that have been extensively evaluated, BRCA1, BRCA2, PALB2 and BRIP1 stand as examples where the majority of mutations lead to protein truncation;TP53 provides a counter example, where the majority of pathogenic variants are missense substitutions. In ATM and CHEK2, missense substitutions are probably equally or more important in terms of their frequency and attributable risk. Therefore, ongoing efforts to identify new susceptibility genes should not ignore missense variation.

Keywords::

• ATM
• BRCA1
• BRCA2
• breast cancer
• CHEK2
• genetic susceptibility
• homologous recombination repair
• missense substitution
• rare variant
• unclassified variant

Disclaimer

The content of this review does not necessarily reflect the views or policies of the National Cancer Institute (NCI), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Financial & competing interests disclosure

G Chenevix-Trench is supported by grants from the Australian National Health and Medical Research Council and the Susan G. Komen Foundation. SV Tavtigian is supported by grants from the US NIH and also receives royalties from the NIH that originate from Myriad Genetics' BRACAnalysis testing. Work described here was also supported in part by NIH NCI R01CA121245. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

G Chenevix-Trench is supported by grants from the Australian National Health and Medical Research Council and the Susan G. Komen Foundation. SV Tavtigian is supported by grants from the US NIH and also receives royalties from the NIH that originate from Myriad Genetics' BRACAnalysis testing. Work described here was also supported in part by NIH NCI R01CA121245. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.