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Cancer Research and Treatment > Accepted Articles
doi: https://doi.org/10.4143/crt.2016.433    [Accepted]
Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls
Ji Soo Park1.2, Eun Ji Nam1,3, Hyung Seok Park1,4, Jung Woo Han1,5, Jung-Yun Lee1,3, Jieun Kim6, Tae Il Kim1,7, Seung-Tae Lee1,6
1Hereditary Cancer Clinic, Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
2Department of Medicine, The Graduate School of Yonsei University, Yonsei University College of Medicine, Seoul, Korea
3Institute of Women’s Life Medical Science, Women’s Cancer Clinic, Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Korea
4Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
5Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
6Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
7Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
Correspondence  Seung-Tae Lee ,Tel: 82-2-2228-2450, Fax: 82-2-364-1583, Email: LEE.ST@yuhs.ac
Received: September 6, 2016;  Accepted: January 2, 2017.  Published online: January 17, 2017.
ABSTRACT
Purpose
Comparison of variant frequencies in the general population has become an essential part of the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for interpreting sequence variants. We determined the optimal number of relevant ethnic controls that should be used to accurately calculate the odds ratio (OR) of genetic variants.
Materials and Methods
Using the ACMG guidelines, we reclassified BRCA1 and BRCA2 mutations and variants of unknown significance in 745 Korean patients susceptible to hereditary breast and ovarian cancer compared with 1,314 Korean population controls.
Results
We observed that the ORs were falsely inflated when we analyzed several variants using non-Korean population data. Our simulation indicated that the number of controls needed for the lower limit of a 95% confidence interval to exceed 1.0 varied according to the frequency of the variant in each patient group, with more than 820 controls needed for a variant existing in 1% of cases. Using a sufficient number of relevant population data, we could efficiently classify variants and identified the BRCA1 Leu1780Pro mutation as a possible pathogenic founder mutation in Korean patients.
Conclusion
Our study suggests that BRCA1 Leu1780Pro is a novel pathogenic mutation found in Korean patients. We also determined the optimal number of relevant ethnic controls needed for accurate variant classification according to the ACMG guidelines.
Key words: BRCA1, BRCA2, ACMG standards and guidelines, Korean, Leu1780Pro
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