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Breast Cancer Research
Published in: Breast Cancer Research 1/2009

Open Access 01-06-2009 | Research article

A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2genes based on cancer family history

Authors: Encarna B Gómez García, Jan C Oosterwijk, Maarten Timmermans, Christi J van Asperen, Frans BL Hogervorst, Nicoline Hoogerbrugge, Rogier Oldenburg, Senno Verhoef, Charlotte J Dommering, Margreet GEM Ausems, Theo AM van Os, Annemarie H van der Hout, Marjolijn Ligtenberg, Ans van den Ouweland, Rob B van der Luijt, Juul T Wijnen, Jan JP Gille, Patrick J Lindsey, Peter Devilee, Marinus J Blok, Maaike PG Vreeswijk

Published in: Breast Cancer Research | Issue 1/2009

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Abstract

Introduction

Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs.

Methods

We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families).

Results

The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p.S1655F, p.R1699W, and p.R1699Q variants in BRCA1 and the p.Y2660D, p.R2784Q, and p.R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p.L246V variant in BRCA1 and of the p.Y42C, p.E462G, p.R2888C, and p.R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p.R2784W variant in BRCA2 remains uncertain.

Conclusions

The present study shows that these developed models are useful to classify UVs in clinical genetic practice.
Appendix
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Metadata
Title
A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2genes based on cancer family history
Authors
Encarna B Gómez García
Jan C Oosterwijk
Maarten Timmermans
Christi J van Asperen
Frans BL Hogervorst
Nicoline Hoogerbrugge
Rogier Oldenburg
Senno Verhoef
Charlotte J Dommering
Margreet GEM Ausems
Theo AM van Os
Annemarie H van der Hout
Marjolijn Ligtenberg
Ans van den Ouweland
Rob B van der Luijt
Juul T Wijnen
Jan JP Gille
Patrick J Lindsey
Peter Devilee
Marinus J Blok
Maaike PG Vreeswijk
Publication date
01-06-2009
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2009
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2223

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