Impact of proactive high-throughput functional assay data on BRCA1 variant interpretation in 3684 patients with breast or ovarian cancer

• Published in: Journal of human genetics Vol. 65; no. 3; pp. 209 - 220
• Main Authors: Kim, Hyun-Ki, Lee, Eun Jin, Lee, Young-Jae, Kim, Jisun, Kim, Yongsub, Kim, Kyunggon, Lee, Shin-Wha, Chang, Suhwan, Lee, Young Joo, Lee, Jong Won, Lee, Woochang, Chun, Sail, Son, Byung Ho, Jung, Kyung Hae, Kim, Yong-Man, Min, Won-Ki, Ahn, Sei-Hyun
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2020
• Subjects: Adult; Aged; Amino acids; AMP; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - epidemiology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Classification; Family medical history; Female; Genetic diversity; Genetic Predisposition to Disease; Genetic screening; Genetic Testing; Genetic Variation - genetics; Genetics; Genotype; Genotyping; Germ-Line Mutation - genetics; Humans; Laboratories; Medical schools; Medicine; Middle Aged; Mutation, Missense - genetics; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - epidemiology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Patients; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Poly(ADP-ribose) Polymerases - genetics; Proteins; Reclassification; Republic of Korea - epidemiology; Ribose; Stem cells; Studies; Republic of Korea
• DOI: 10.1038/s10038-019-0713-2
• ISSN: 1434-5161

The clinical utility of BRCA1/2 genotyping was recently extended from the selection of subjects at high risk for hereditary breast and ovary cancer to the identification of candidates for poly (ADP-ribose) polymerase (PARP) inhibitor treatment. This underscores the importance of accurate interpretation of BRCA1/2 genetic variants and of reducing the number of variants of uncertain significance (VUSs). Two recent studies by Findlay et al. and Starita et al. introduced high-throughput functional assays, and proactively analyzed variants in specific regions regardless of whether they had been previously observed. We retrospectively reviewed all BRCA1 and BRCA2 germline genetic test reports from patients with breast or ovarian cancer examined at Asan Medical Center (Seoul, Korea) between September 2011 and December 2018. Variants were assigned pathogenic or benign strong evidence codes according to the functional classification and were reclassified according to the ACMG/AMP 2015 guidelines. Among 3684 patients with available BRCA1 and BRCA2 germline genetic test reports, 429 unique variants (181 from BRCA1) were identified. Of 34 BRCA1 variants intersecting with the data reported by Findlay et al., three missense single-nucleotide variants from four patients (0.11%, 4/3684) were reclassified from VUSs to likely pathogenic variants. Four variants scored as functional were reclassified into benign or likely benign variants. Three variants that overlapped with the data reported by Starita et al. could not be reclassified. In conclusion, proactive high-throughput functional study data are useful for the reclassification of clinically observed VUSs. Integrating additional evidence, including functional assay results, may help reduce the number of VUSs.