Suggestion of BRCA1 c.5339T>C (p.L1780P) variant confer from ‘unknown significance’ to ‘Likely pathogenic’ based on clinical evidence in Korea

Purpose We describe a rationale for the re-classification of the BRCA1 c.5539T>C (L1780P) variant using a clinical evidence. Methods A retrospective review was conducted to identify all patients with breast or ovarian cancer and the L1780P variant between 2002 and 2015 at a single institution. Results We identified the BRCA1/2 genetic mutation test results of 1223 breast cancer patients and 174 patients with ovarian cancer. Of the 160 BRCA 1/2 variant unknown significance, 16 (10.0%) patients were identified as having the L1780P variant. Among them, 10 had breast cancer, 4 had ovarian cancer, and 2 had both breast and ovarian cancer. Thirteen (81.3%) patients with this variant had family histories of breast or ovarian cancer. Two (16.7%) also had comorbid ovarian cancer. Two patients with this variant showed that co-segregation of the disease in multiple family members and family histories of breast and ovarian cancer. This variant was found to be either absent or at extremely low frequency in general population databases. Conclusion The L1780P variant might confer to “Likely pathogenic” according to a clinical evidence and the ACMG standards and guidelines. A nation-wide or global survey and a functional analysis are needed to confirm the pathogenicity of the L1780P variant.