title: Exome Sequencing in a Family with Luminal-Type Breast Cancer Underpinned by Variation in the Methylation Pathway.
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 twoBRCA1/2mutation-negative breast cancer patients from the same family for WES. Homozygosity for theMTHFR677 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 theRAD50R385C 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.
authors.affiliation: Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7500, South Africa. vmrnic015@myuct.ac.za.
authors.forename: Nicole
authors.initials: N
authors.lastname: van der Merwe
authors.affiliation: Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7500, South Africa. avpeeters@sun.ac.za.
authors.forename: Armand V
authors.initials: AV
authors.lastname: Peeters
authors.affiliation: GVI Oncology, Mediclinic Panorama, Cape Town 8000, South Africa. rika.pienaar@cancercare.co.za.
authors.forename: Fredrieka M
authors.initials: FM
authors.lastname: Pienaar
authors.affiliation: Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7500, South Africa. jbez@sun.ac.za.
authors.forename: Juanita
authors.initials: J
authors.lastname: Bezuidenhout
authors.affiliation: Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7500, South Africa. sjvr@sun.ac.za.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: van Rensburg
authors.affiliation: Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7500, South Africa. maritha@sun.ac.za.|National Health Laboratory Service, Tygerberg Hospital, Tygerberg 7500, South Africa. maritha@sun.ac.za.
authors.forename: Maritha J
authors.initials: MJ
authors.lastname: Kotze
mesh_terms: D017766:Acid Anhydride Hydrolases; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D014644:Genetic Variation; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes
keywords: breast cancer; exome sequencing; methylation pathway; pathology; pharmacogenomics