Comprehensive evidence for the pathogenicity of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in Japanese hereditary breast and ovarian cancer.

Reclassification of BRCA2 c.7847C>T (p.Ser2616Phe) VUS — Japanese-specific — as Pathogenic by quantitative cosegregation, three functional assays (MANO, HDR, SGE), and a Fanconi anemia case

A BRCA2 variant long classified as uncertain significance (c.7847C>T; p.Ser2616Phe), specific to the Japanese population, was reclassified as Pathogenic through a nationwide study of 44 carriers from 35 distinct families. Quantitative cosegregation yielded a combined likelihood ratio of ≈60 (PP1_Strong), supported by three robust functional assays — MANO, HDR, and saturation genome editing (PS3) — and a Fanconi anemia case (PM3_Moderate). This reclassification is critical as BRCA1/2 serves as a companion diagnostic for PARP inhibitor access in Japan.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This study perfectly illustrates the power of a national collaborative approach to reclassify challenging VUS. The c.7847C>T variant is rare in global gnomAD (6.20×10⁻⁷) but present at 1.06×10⁻⁴ in the Japanese ToMMo database — a population founder variant. The convergence of cosegregation + SGE + HDR meets the evidentiary standard required by the ClinGen ENIGMA VCEP. A model to replicate for other founder variants in underrepresented populations.

Clinical impact: 3/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 0/1 · Journal quality: 1/1 → Total: 8/10