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Int. J. Mol. Sci. 2017, 18(2), 467; doi:10.3390/ijms18020467

Exome Sequencing in a Family with Luminal-Type Breast Cancer Underpinned by Variation in the Methylation Pathway

1
Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7500, South Africa
2
GVI Oncology, Mediclinic Panorama, Cape Town 8000, South Africa
3
Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7500, South Africa
4
National Health Laboratory Service, Tygerberg Hospital, Tygerberg 7500, South Africa
*
Author to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 2 January 2017 / Revised: 31 January 2017 / Accepted: 10 February 2017 / Published: 22 February 2017
(This article belongs to the Special Issue Next-Generation Sequencing for Clinical Application)
View Full-Text   |   Download PDF [2660 KB, uploaded 22 February 2017]   |  

Abstract

Panel-based next generation sequencing (NGS) is currently preferred over whole exome sequencing (WES) for diagnosis of familial breast cancer, due to interpretation challenges caused by variants of uncertain clinical significance (VUS). There is also no consensus on the selection criteria for WES. In this study, a pathology-supported genetic testing (PSGT) approach was used to select two BRCA1/2 mutation-negative breast cancer patients from the same family for WES. Homozygosity for the MTHFR 677 C>T mutation detected during this PSGT pre-screen step was considered insufficient to cause bilateral breast cancer in the index case and her daughter diagnosed with early-onset breast cancer (<30 years). Extended genetic testing using WES identified the RAD50 R385C missense mutation in both cases. This rare variant with a minor allele frequency (MAF) of <0.001 was classified as a VUS after exclusion in an affected cousin and extended genotyping in 164 unrelated breast cancer patients and 160 controls. Detection of functional polymorphisms (MAF > 5%) in the folate pathway in all three affected family members is consistent with inheritance of the luminal-type breast cancer in the family. PSGT assisted with the decision to pursue extended genetic testing and facilitated clinical interpretation of WES aimed at reduction of recurrence risk. View Full-Text
Keywords: breast cancer; exome sequencing; methylation pathway; pathology; pharmacogenomics breast cancer; exome sequencing; methylation pathway; pathology; pharmacogenomics
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MDPI and ACS Style

van der Merwe, N.; Peeters, A.V.; Pienaar, F.M.; Bezuidenhout, J.; van Rensburg, S.J.; Kotze, M.J. Exome Sequencing in a Family with Luminal-Type Breast Cancer Underpinned by Variation in the Methylation Pathway. Int. J. Mol. Sci. 2017, 18, 467.

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