RT Journal Article SR Electronic T1 Reclassification of BRCA1 and BRCA2 variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 794 OP 802 DO 10.1136/jmedgenet-2018-105565 VO 55 IS 12 A1 Jee-Soo Lee A1 Sohee Oh A1 Sue Kyung Park A1 Min-Hyuk Lee A1 Jong Won Lee A1 Sung-Won Kim A1 Byung Ho Son A1 Dong-Young Noh A1 Jeong Eon Lee A1 Hai-Lin Park A1 Man Jin Kim A1 Sung Im Cho A1 Young Kyung Lee A1 Sung Sup Park A1 Moon-Woo Seong YR 2018 UL http://jmg.bmj.com/content/55/12/794.abstract AB Background BRCA1 and BRCA2 (BRCA1/2) variants classified ambiguously as variants of uncertain significance (VUS) are a major challenge for clinical genetic testing in breast cancer; their relevance to the cancer risk is unclear and the association with the response to specific BRCA1/2-targeted agents is uncertain. To minimise the proportion of VUS in BRCA1/2, we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer.Methods We used a data set of 2115 patients with breast cancer from the nationwide multicentre prospective Korean Hereditary Breast Cancer study. In total, 83 BRCA1/2 VUSs (BRCA1, n=26; BRCA2, n=57) were analysed. The multifactorial probability was estimated by combining the prior probability with the overall likelihood ratio derived from co-occurrence of each VUS with pathogenic variants, personal and family history, and tumour characteristics. The classification was compared with the interpretation according to the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG/AMP) guidelines. An external validation was conducted using independent data set of 810 patients.Results We were able to redefine 38 VUSs (BRCA1, n=10; BRCA2, n=28). The revised classification was highly correlated with the ACMG/AMP guideline-based interpretation (BRCA1, p for trend=0.015; BRCA2, p=0.001). Our approach reduced the proportion of VUS from 19% (154/810) to 8.9% (72/810) in the retrospective validation data set.Conclusion The classification in this study would minimise the ‘uncertainty’ in clinical interpretation, and this validated multifactorial model can be used for the reliable annotation of BRCA1/2 VUSs.