A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity

Lucia Guidugli, Vernon S. Pankratz, Namit Singh, James Thompson, Catherine A. Erding, Christoph Engel, Rita Schmutzler, Susan Domchek, Katherine Nathanson, Paolo Radice, Christian Singer, Patricia N. Tonin, Noralane M. Lindor, David E. Goldgar, Fergus J. Couch

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Abstract

The relevance of many BRCA2 variants of uncertain significance (VUS) to breast cancer has not been determined due to limited genetic information from families carrying these alterations. Here, we classified six new variants as pathogenic or nonpathogenic by analysis of genetic information from families carrying 64 individual BRCA2 DNA binding domain (DBD) missense mutations using a multifactorial likelihood model of cancer causality. Next, we evaluated the use of a homology-directed DNA break repair (HDR) functional assay as a method for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD. Compared with the known status of these variants based on the multifactorial likelihood model, the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% [95% confidence interval (CI): 75.3%-100%] and specificity was estimated at 100% (95% CI: 81.5%-100%). A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results. When applied to 33 additional VUS, the classifier identified eight with 99% or more probability of nonpathogenicity and 18 with 99% or more probability of pathogenicity. Thus, in the absence of genetic evidence, a cell-based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD, suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS.

Original languageEnglish
Pages (from-to)265-275
Number of pages11
JournalCancer Research
Volume73
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

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DNA Breaks
DNA Repair
DNA
Virulence
Missense Mutation
Confidence Intervals
Causality
Neoplasms
Breast Neoplasms
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Guidugli, L., Pankratz, V. S., Singh, N., Thompson, J., Erding, C. A., Engel, C., ... Couch, F. J. (2013). A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Research, 73(1), 265-275. https://doi.org/10.1158/0008-5472.CAN-12-2081

A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. / Guidugli, Lucia; Pankratz, Vernon S.; Singh, Namit; Thompson, James; Erding, Catherine A.; Engel, Christoph; Schmutzler, Rita; Domchek, Susan; Nathanson, Katherine; Radice, Paolo; Singer, Christian; Tonin, Patricia N.; Lindor, Noralane M.; Goldgar, David E.; Couch, Fergus J.

In: Cancer Research, Vol. 73, No. 1, 01.01.2013, p. 265-275.

Research output: Contribution to journalArticle

Guidugli, L, Pankratz, VS, Singh, N, Thompson, J, Erding, CA, Engel, C, Schmutzler, R, Domchek, S, Nathanson, K, Radice, P, Singer, C, Tonin, PN, Lindor, NM, Goldgar, DE & Couch, FJ 2013, 'A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity', Cancer Research, vol. 73, no. 1, pp. 265-275. https://doi.org/10.1158/0008-5472.CAN-12-2081
Guidugli, Lucia ; Pankratz, Vernon S. ; Singh, Namit ; Thompson, James ; Erding, Catherine A. ; Engel, Christoph ; Schmutzler, Rita ; Domchek, Susan ; Nathanson, Katherine ; Radice, Paolo ; Singer, Christian ; Tonin, Patricia N. ; Lindor, Noralane M. ; Goldgar, David E. ; Couch, Fergus J. / A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. In: Cancer Research. 2013 ; Vol. 73, No. 1. pp. 265-275.
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