Cancer Res Treat.  2017 Jul;49(3):627-634. 10.4143/crt.2016.292.

Clinically Significant Unclassified Variants in BRCA1 and BRCA2 genes among Korean Breast Cancer Patients

• Yoon KA
• Park B
• Lee BI
• Yang MJ
• Kong SY
• Lee ES

• KMID: 2388308
• DOI: http://doi.org/10.4143/crt.2016.292

Abstract

PURPOSE
Unclassified variants (UVs) of BRCA1 and BRCA2 genes are not defined as pathogenic for breast cancer, and their clinical significance currently remains undefined. Therefore, this study was conducted to identify potentially pathogenic UVs by comparing their prevalence between breast cancer patients and controls.
MATERIALS AND METHODS
A total of 328 breast cancer patients underwent BRCA1/2 genetic screening at the National Cancer Center of Korea. Genetic variants of BRCA genes that were categorized as unclassified according to the Breast Cancer Information Core database were selected based on allelic frequency, after which candidate variants were genotyped in 421 healthy controls. We also examined family members of the study participants. Finally, the effects of amino acid substitutions on protein structure and function were predicted in silico.
RESULTS
Genetic tests revealed 33 UVs in BRCA1 and 47 in BRCA2. Among 15 candidates genotyped in healthy controls, c.5339T>C in BRCA1 and c.6029T>G, c.7522G>A in BRCA2 were not detected. Moreover, the c.5339T>C variant in the BRCA1 gene was detected in four patients with a family history of breast cancer. This nonsynonymous variant (Leu1780Pro) in the BRCA1 C-terminal domain was predicted to have an effect on BRCA1 protein structure/function.
CONCLUSION
This study showed that comparison of genotype frequency between cases and controls could help identify UVs of BRCA genes that are potentially pathogenic. Moreover, ourfindings suggest that c.5339T>C in BRCA1 might be a pathogenic variant for patients and their families.

Keyword

Familial breast cancer; BRCA1; BRCA2; Unclassified variants

MeSH Terms

Amino Acid Substitution
BRCA1 Protein
Breast Neoplasms*
Breast*
Computer Simulation
Genes, BRCA1
Genes, BRCA2*
Genetic Testing
Genotype
Humans
Korea
Prevalence
BRCA1 Protein

Figure

• 

  Fig. 1. Unclassified variant c.5339T>C in BRCA1. The candidate UV, c.5339T>C, was tested in breast cancer patients and family members (A, B). Red in each pedigree indicates a carrier of the variant genotype, while green indicates family members without the variant. The proband of each family is indicated by a black arrow. (C) Predicted structure of BRCA1 variant (Leu1780Pro) in the BRCA1 C-terminal (BRCT) domain. Left, overall structure of the BRCT domain of BRCA1; right, detailed view of the region surrounding the variant. Hydrophobic residues around Leu1780 are shown and labeled in red.

Reference

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