Comprehensive evidence for the pathogenicity of the BRCA2 c.7847C>T (p.Ser2616Phe) variant specific to the Japanese...

The BRCA2 c.7847C>T (p.Ser2616Phe) variant is specific to the Japanese population and has long remained a variant of uncertain significance. Because BRCA1/2 genetic testing serves as a companion diagnostic for poly (ADP-ribose) polymerase inhibitor therapy in Japan, unresolved classification has limited access to targeted treatment.

We conducted a nationwide study using the national Hereditary Breast and Ovarian Cancer registry. Pathogenicity was assessed through quantitative cosegregation analysis, a systematic review of functional and clinical evidence and evaluation of variant frequency in population databases. Evidence was integrated using the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel framework.

We identified 44 carriers from 35 distinct Japanese families. Quantitative cosegregation analysis yielded a combined likelihood ratio of approximately 60, satisfying the PP1_Strong criterion. This was supported by robust evidence from multiple functional studies, including Mixed-All-Nominated-in-One-BRCA, homology-directed repair and saturation genome editing assays (PS3) and a reported case of Fanconi anaemia (PM3_Moderate). This variant is rare, with an allele frequency of 6.20×10^-7 in gnomAD and 1.06×10^-4 in ToMMo 61KJPN (PM2_Supporting). Although the BayesDel noAF score met the benign criterion (BP4), other in silico tools indicated deleterious effects. In total, the accumulated evidence reached 10 points, corresponding to an estimated odds of pathogenicity of 895:1, exceeding the 'Pathogenic' threshold.

By integrating newly collected genetic data with functional and clinical evidence, we provide robust support for reclassifying the BRCA2 c.7847C>T (p.Ser2616Phe) variant as 'Pathogenic'. This reclassification is crucial for ensuring that eligible Japanese patients gain access to appropriate targeted therapies.