Comprehensive evidence for the pathogenicity of the BRCA2 c.7847C>T (p.Ser2616Phe) variant specific to the Japanese population - PubMed
5 hours ago
- #Japanese Population
- #BRCA2
- #Genetic Testing
- The BRCA2 c.7847C>T (p.Ser2616Phe) variant is specific to the Japanese population and was previously classified as a variant of uncertain significance.
- A nationwide study using the Hereditary Breast and Ovarian Cancer registry identified 44 carriers from 35 distinct Japanese families.
- Quantitative cosegregation analysis yielded a combined likelihood ratio of approximately 60, meeting the PP1_Strong criterion for pathogenicity.
- Functional studies, including Mixed-All-Nominated-in-One-BRCA and homology-directed repair assays, supported the variant's pathogenicity (PS3).
- The variant is rare, with an allele frequency of 6.20×10-7 in gnomAD and 1.06×10-4 in ToMMo 61KJPN (PM2_Supporting).
- Accumulated evidence reached 10 points, corresponding to an estimated odds of pathogenicity of 895:1, exceeding the 'Pathogenic' threshold.
- The study concludes that the BRCA2 c.7847C>T (p.Ser2616Phe) variant should be reclassified as 'Pathogenic' to ensure Japanese patients gain access to targeted therapies.