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Lee, Jang, Lee, Yoon, Lee, Kim, and Kong: Status of BRCA1/2 Genetic Testing Practices in Korea (2014)
Original Article

Lab Med Online 2018;8(3):107-113.

Published online: 19 July 2018

DOI: https://doi.org/10.3343/lmo.2018.8.3.107

Status of BRCA1/2 Genetic Testing Practices in Korea (2014)

Kyungju Lee1, Ja-Hyun Jang, M.D.2, Seung-Tae Lee, M.D.3, Kyong-Ah Yoon, Ph.D.4, Eun Sook Lee, M.D.5, 6, 7, Jong-Won Kim, M.D.8, Sun-Young Kong, M.D.5, 9

1Common Cancer Branch Research Institute, National Cancer Center, Goyang, Korea

2Green Cross Genome, Yongin, Korea

3Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea

4College of Veterinary Medicine, Konkuk University, Seoul, Korea

5National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea

6Center for Breast Cancer, Hospital, National Cancer Center, Goyang, Korea

7Immunotherapeutics Branch, Research Institute, National Cancer Center, Goyang, Korea

8Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

9Department of Laboratory Medicine9, National Cancer Center, Goyang, Korea

Corresponding author: Sun-Young Kong Department of Laboratory Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel: +82-31-920-1735, Fax: +82-31-920-1339, E-mail: ksy@ncc.re.kr

Received 28 August 2017       Revised 31 October 2017       Accepted 21 December 2017

Copyright © 2018 The Korean Society for Laboratory Medicine

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background:

The aim of this study was to investigate the status of BRCA1/2 genetic testing practices in Korea in 2014.

Methods:

A structured questionnaire was provided to the specialist in charge of BRCA1/2 genetic testing via e-mail between 28 July and 10 August 2015. A total of 11 genetic testing professionals from 14 organizations responded to the survey that asked about the status of BRCA1/2 genetic testing in the year 2014.

Results:

The average number of BRCA1/2 genetic tests executed was 192; 6 organizations had executed less than 100 tests, and 5 organizations had conducted more than 100 tests. The primary testing method used was Sanger sequencing (100%), and 2 institutes performed multiplex ligation-dependent probe amplification (MLPA). The analysis software differed across the various organizations, with Sequencher (81.81%), Seqscape (27.27%), and Codoncode Aligner (9.09%) reported as utilized. We found that the guidelines for the interpretation of the genetic tests were different at each institution.

Conclusions:

Although this study only examined the status of the 2014 BRCA1/2 genetic testing practices of 11 institutions, it illustrates the necessity for standardized genetic testing or interpretation guidelines in Korea.

Keywords: Genes, BRCA1, BRCA2, Questionnaires and Surveys, Genetic testing, Standardization

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Table 1.
Survey questionnaires and answer frequencies
Questionnaires & Answer Options Answer N (%)
1 How many BRCA1/2 genetic tests were conducted at your institution in 2014?
  A. <100 6 (54.55)
  B. ≥100 5 (45.45)
2 What method(s) does your organization use to perform genetic testing?∗
  A. Sanger sequencing (direct sequencing of whole exons) 11 (100.00)
  B. Multiplex ligation-dependent probe amplification (MLPA) 2 (18.18)
  C. Mutation scanning 0 (0)
  D. Pyrosequencing 0 (0)
3 What type of software does your organization use to analyze the genetic testing results?∗
  A. Sequencher 9 (81.81)
  B. Seqscape 3 (27.27)
  C. Seqscanner 0 (0)
  D. Mutation surveyor 0 (0)
  E. GENETYX 0 (0)
  F. MT Navigator 0 (0)
  G. CLC Genomics/Main workbench 0 (0)
  H. Nextgene 0 (0)
  I. Others (CodonCode Aligner) 1 (9.09)
4 What percentages of BRCA pathogenic variants and VUS detection (prevalence) rates did your institution have in 2014?∗∗
  A. Pathogenic variant mutation: _______% 18.1 (mean)
  B. VUS: _______% 20.5 (mean)
5 Do you have any criteria for interpreting the results of the BRCA1/2 genetic tests at your institution?∗
  A. ACMG guideline 9 (81.82)
  B. IARC guideline 3 (27.27)
  C. Modified version of previous guideline 3 (27.27)
  D. No 0 (0)
6 W hat numbering system does your organization follow for the genetic test report?  
  A. HGVS nomenclature 8 (72.72)
  B. BIC nomenclature 1 (9.09)
  C. HGVS nomenclature & BIC nomenclature 2 (18.19)
7 What kind of database does your organization utilize for the clinical interpretation of the pathogenic variants found from the results of the genetic tests?∗
  A. Human Gene Mutation Database (HGMD) 11 (100.00)
  B. Breast Cancer Information Code (BIC) 11 (100.00)
  C. ClinVar 10 (90.91)
  D. DbSNP 10 (90.91)
  E. Literature search 8 (72.73)
  F. LOVD-IARC 7 (63.64)
  G. Leiden Open Variation Database 4 (36.36)
  H. Organization's own database 3 (27.27)
  I. ARUP BRCA1/2 Mutation Database 2 (18.18)
  J. Korean Breast Cancer Registry Database 2 (18.18)
  K. BRCA1/2 Share 0 (0)
8 Based on the clinical significance of the pathogenic variants found from your genetic testing results, how many categories do you use and how do you name them?∗∗∗
  A. 3 11 (100.00)
  B. 5 0 (0)
  C. 6 0 (0)
9 What type of clinical information is referenced when interpreting the genetic testing results?∗
  A. Family history 8 (72.73)
  B. Age of cancer onset 7 (63.64)
  C. Pathological result 3 (27.27)
  D. Do not exploit references 3 (27.27)
  E. Unilateral/bilateral 1 (9.09)
10 Do you consider the population frequency of the pathogenic variants obtained from genetic testing as an important factor? If so, what type of reference method do you use?∗
  A. 1000 Genome frequency 6 (54.55)
  B. Racial (ethnicity) frequency 6 (54.55)
  C. Korean frequency 6 (54.55)
  D. Hapmap frequency 5 (45.45)
  E. Not important 2 (18.18)
11 What criterion is used to decide common SNPs, when using the population frequency as a reference? What standard percentage is used for the allele frequency?
  A. No criteria 2 (18.18)
  B. DbSNP-common SNP 3 (27.27)
  C. 1% 5 (45.45)
  D. 5% 1 (9.09)
12 How do you report pathogenic variants that have already been identified in existing papers or listed in the pathogenic variant database?
  A. Always report as a pathogenic variant 2 (18.18)
  B. Additional review and classified as VUS if unclassified/unclear result 9 (81.82)
13 Do you report the degree of risk based on the genetic testing results?
  A. No 7 (63.64)
  B. Increasing risk level/normal range 4 (36.36)
  C. Calculation of risk value 0 (0)
14 What analytical tool do you use to perform the in-silico analysis regarding a VUS?∗
  A. PolyPhen-2 11 (100.00)
  B. SIFT 10 (90.91)
  C. Align-GVGD 6 (54.55)
  D. Splicing analysis 4 (36.36)
  E. Mutation Taster 3 (27.27)
  F. FATHMN 1 (9.09)
  G. Mutation Assessor 0 (0)
  H. GERP++ 0 (0)
  I. No in-silico analysis 0 (0)
15 If you performed an in-silico analysis, do you indicate this method in the results report?
  A. Yes 8 (72.73)
  B. No 3 (27.27)
16 How do you interpret the synonymous variation derived from a VUS observed in the genetic test results?
  A. All negative 2 (18.18)
  B. All VUS 0 (0)
  C. VUS and additional statement of a low possibility of a pathogenic variant 3 (27.27)
  D. VUS based on population frequency, in-silico study, and references 5 (45.45)
  E. No case of VUS, synonymous 1 (9.09)
17 How do you interpret the MISSENSE VARIATION derived from a VUS observed in the genetic test results?
  A. All positive 0 (0)
  B. All VUS 0 (0)
  C. VUS based on population frequency, in-silico study, and references 10 (90.91)
  D. VUS-based, but provide objective evidence, such as population frequency, in-silico study, and literature reports for clinician determination. 1 (9.09)
18 How do you interpret INTRONIC VARIATION other than the splice site of VUS observed in the genetic test results?
  A. All positive 0 (0)
  B. All VUS 0 (0)
  C. VUS and additional statement of a low possibility of a pathogenic variant 5 (45.45)
  D. VUS based on population frequency, in-silico study, and references 5 (45.45)
  E. Additional RNA studies 1 (9.09)
19 If you find any pathogenic variants that are unclear based on your clinical judgement, do you recommend testing for the patient's family?
  A. Yes 8 (72.73)
  B. No 3 (27.27)
20 Do o you consider the prerequisite of the 5-step reporting system for a VUS?  
  A. Yes 0 (0)
  B. Yes, but it is not practical 8 (72.73)
  C. Yes, if it is necessary in clinical practice 3 (27.27)
  D. No 0 (0)
21 Are you willing to follow the Korean version of standardization and guidelines for BRCA1/2 genetic testing in the future?
  A. Yes 6 (54.55)
  B. Yes, if it is practical in a clinical setting 5 (45.45)
  C. Not yet 0 (0)
22 What do you think is indispensable for the standardized interpretation of BRCA1/2 genetic test results in Korean clinical practice?∗
  A. Korean polymorphism database 11 (100.00)
  B. Functional study database 8 (72.73)
  C. Objective criteria of interpretation 11 (100.00)

∗ Multiple answers possible;

∗∗ Open-ended answer, the answers are shown in Table 2;

∗∗∗ Open-ended answer, the answers are shown in Table 3.

Table 2.
Pathogenic variant and variation of unknown significance (VUS) detection rates for each organization in 2014
(%) A B C D E F G H I J K
Pathogenic variant 17 15 20.9 14.8 18 32/8.3∗ 20 22 5 10 16
VUS 29 30 9 29.6 14 0 42.5 18 10 10 33

∗ BRCA1/2: 32%, BRCA1/2: 8.3%.

Table 3.
Category names used for the variants in the genetic test results
  A B C D E F G H I J K
1 Polymorphism Detected Benign Benign variant No pathogenic variant detected Benign variant Polymorphism Polymorphism Pathogenic variant Benign variant Benign
2 Unclassified variant VOUS∗ detected VUS∗ Variant of uncertain significance Variant of uncertain significance Variant of uncertain significance Variant of uncertain significance Unclassified Variant Unclassified Variant Variant of uncertain significance VUS∗
3 Pathogenic variant Not detected Pathogenic variant Pathogenic variant Pathogenic variant detected Pathogenic variant Pathogenic variant Pathogenic variant Polymorphism Pathogenic variant Pathogenic

All of the organizations used 3 categories. ∗variants of unknown (or uncertain) significance.

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