title: 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.
abstract: OBJECTIVE
  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.
  
  
  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 p.Leu1780Pro mutation as a possible pathogenic founder mutation in Korean patients.
  
  
  CONCLUSIONS
  Our study suggests that BRCA1 p.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.
authors.affiliation: Hereditary Cancer Clinic, Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Department of Medicine, The Graduate School of Yonsei University, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Ji Soo
authors.initials: JS
authors.lastname: Park
authors.affiliation: Hereditary Cancer Clinic, Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Women's Cancer Clinic, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Nam
authors.affiliation: Hereditary Cancer Clinic, Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyung Seok
authors.initials: HS
authors.lastname: Park
authors.affiliation: Hereditary Cancer Clinic, Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Han
authors.affiliation: Hereditary Cancer Clinic, Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Women's Cancer Clinic, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jung-Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Hereditary Cancer Clinic, Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Tae Il
authors.initials: TI
authors.lastname: Kim
authors.affiliation: Hereditary Cancer Clinic, Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Seung-Tae
authors.initials: ST
authors.lastname: Lee
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D016017:Odds Ratio; D011159:Population Surveillance; D011487:Protein Conformation; D056910:Republic of Korea / Q000453:epidemiology; D013329:Structure-Activity Relationship; D000073359:Exome Sequencing
chemical_list: D014408:Biomarkers, Tumor
keywords: ACMG standards and guidelines; BRCA1; BRCA2; Korean; Leu1780Pro