Cancer Res Treat.  2017 Oct;49(4):1012-1021. 10.4143/crt.2016.433.

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

• Park JS
• Nam EJ
• Park HS
• Han JW
• Lee JY
• Kim J
• Kim TI
• Lee ST

• KMID: 2394820
• DOI: http://doi.org/10.4143/crt.2016.433

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 p.Leu1780Pro mutation as a possible pathogenic founder mutation in Korean patients.
CONCLUSION
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.

Keyword

BRCA1; BRCA2; ACMG standards and guidelines; Korean; Leu1780Pro

MeSH Terms

Breast
Classification
Genetics, Medical
Genomics
Humans
Odds Ratio
Ovarian Neoplasms
Population Control

Figure

• 

  Fig. 1. Odd ratios (ORs) calculations using different population data. Comparison of cases with non-Finnish Europeans (NFE) from Exome Aggregation Consortium (ExAC) results in overinflation of ORs. OR inflation was still noted for some benign variants using East Asian (EAS) population data. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Round dots indicate OR and a continuous line through the dot indicates a 95% confidence interval.

• 

  Fig. 2. Structural modeling for BRCA1 p.Leu1780Pro. (A) The p.Leu1780Pro residue is not located on substrate-binding sites and a mutation at this site is not predicted to directly affect interaction with substrates. (B) Rotamer analysis shows that a substitution of the leucine residue for a proline residue with a bulky aromatic side chain causes a clash with adjacent amino acids and disrupts the α-helical structure that maintains the BRCT domain.

• 

  Fig. 3. Simulation to determine the optimal number of subjects for odds ratio calculations. (A) Simulation of the odds ratio and 95% confidence interval for a variant existing in 1% of cases (10 in 1,000 cases) and absent from controls. (B) The number of cases and controls required for the lower limit of a 95% confidence interval to exceed 1.0 varies according to the variant frequency in cases and variant observation in controls.

Reference

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