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01.12.2018 | Research Article | Ausgabe 1/2018 Open Access

Breast Cancer Research 1/2018

Evaluating the breast cancer predisposition role of rare variants in genes associated with low-penetrance breast cancer risk SNPs

Breast Cancer Research > Ausgabe 1/2018
Na Li, Simone M. Rowley, Ella R. Thompson, Simone McInerny, Lisa Devereux, Kaushalya C. Amarasinghe, Magnus Zethoven, Richard Lupat, David Goode, Jason Li, Alison H. Trainer, Kylie L. Gorringe, Paul A. James, Ian G. Campbell
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Electronic supplementary material

The online version of this article (doi:https://​doi.​org/​10.​1186/​s13058-017-0929-z) contains supplementary material, which is available to authorized users.



Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification. On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk.


The coding regions and exon-intron boundaries of 56 genes that have either been proposed by GWASs to be the regulatory targets of the SNPs and/or located < 500 kb from the risk SNPs were sequenced in index cases from 1043 familial breast cancer families that previously had negative test results for BRCA1 and BRCA2 mutations and 944 population-matched cancer-free control participants from an Australian population. Rare (minor allele frequency ≤ 0.001 in the Exome Aggregation Consortium and Exome Variant Server databases) loss-of-function (LoF) and missense variants were studied.


LoF variants were rare in both the cases and control participants across all the candidate genes, with only 38 different LoF variants observed in a total of 39 carriers. For the majority of genes (n = 36), no LoF variants were detected in either the case or control cohorts. No individual gene showed a significant excess of LoF or missense variants in the cases compared with control participants. Among all candidate genes as a group, the total number of carriers with LoF variants was higher in the cases than in the control participants (26 cases and 13 control participants), as was the total number of carriers with missense variants (406 versus 353), but neither reached statistical significance (p = 0.077 and p = 0.512, respectively). The genes contributing most of the excess of LoF variants in the cases included TET2, NRIP1, RAD51B and SNX32 (12 cases versus 2 control participants), whereas ZNF283 and CASP8 contributed largely to the excess of missense variants (25 cases versus 8 control participants).


Our data suggest that rare LoF and missense variants in genes associated with low-penetrance breast cancer risk SNPs may contribute some additional risk, but as a group these genes are unlikely to be major contributors to breast cancer heritability.
Additional file 1: Table S1. Genome coordinates and reported ORs for the breast cancer risk SNPs used in this study. Table S2. Sequencing coverage of 56 candidate genes in case and control cohorts. Table S3. Rare (MAF, < 0.001) missense variants detected in case and control cohorts. Table S4. SNP and rare variant association analysis. (XLSX 111 kb)
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