{
  "abstract": "Background 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.Methods 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.Results 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.Conclusion 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.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Genetics, NHO Tokyo Medical Center, Tokyo, Japan"
      ],
      "name": "Kazuki Yamazawa"
    },
    {
      "affiliations": [
        "Department of Clinical Genetic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan"
      ],
      "name": "Arisa Ueki"
    },
    {
      "affiliations": [
        "Department of Clinical Genetic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan"
      ],
      "name": "Asami Kuga"
    },
    {
      "affiliations": [
        "Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, Japan"
      ],
      "name": "Takao Hinoi"
    },
    {
      "affiliations": [
        "Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, Japan"
      ],
      "name": "Hiroaki Niitsu"
    },
    {
      "affiliations": [
        "Department of Medical Genetics, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan"
      ],
      "name": "Mari Minatogawa"
    },
    {
      "affiliations": [
        "Department of Breast and Thyroid Surgical Oncology, Sagara Hospital, Kagoshima, Japan"
      ],
      "name": "Junko Kawano"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Wakayama Medical University Hospital, Wakayama, Japan"
      ],
      "name": "Sawako Minami"
    },
    {
      "affiliations": [
        "Department of Breast Surgical Oncology, St Luke’s International Hospital, Tokyo, Japan"
      ],
      "name": "Megumi Okawa"
    },
    {
      "affiliations": [
        "Department of Breast Surgical Oncology, St Luke’s International Hospital, Tokyo, Japan"
      ],
      "name": "Junko Takei"
    },
    {
      "affiliations": [
        "Center for Clinical Genetics and Genomic Medicine, Showa Medical University Fujigaoka Hospital, Yokohama, Japan"
      ],
      "name": "Makoto Ichikawa"
    },
    {
      "affiliations": [
        "Department of Breast Surgical Oncology, Showa Medical University Fujigaoka Hospital, Yokohama, Japan"
      ],
      "name": "Katsutoshi Enokido"
    },
    {
      "affiliations": [
        "Department of Breast Surgery, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan",
        "Department of Breast Surgery, Osaka Red Cross Hospital, Osaka, Japan",
        "Department of Breast and Endocrine Surgery, Osaka Breast Clinic, Osaka, Japan"
      ],
      "name": "Noriko Akimaru"
    },
    {
      "affiliations": [
        "Department of Breast Surgery, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan"
      ],
      "name": "Masae Torii"
    },
    {
      "affiliations": [
        "Department of Breast Surgery, Osaka Red Cross Hospital, Osaka, Japan"
      ],
      "name": "Shigeru Tsuyuki"
    },
    {
      "affiliations": [
        "Department of Breast and Endocrine Surgery, Osaka Breast Clinic, Osaka, Japan"
      ],
      "name": "Chikage Iguchi"
    },
    {
      "affiliations": [
        "Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan"
      ],
      "name": "Tazuko Inoue"
    },
    {
      "affiliations": [
        "Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan"
      ],
      "name": "Takeshi Nakajima"
    },
    {
      "affiliations": [
        "Department of Breast and Endocrine Surgery, Osaka International Cancer Institute, Osaka, Japan"
      ],
      "name": "Noriyuki Watanabe"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Yokohama City University Medical Center, Yokohama, Japan"
      ],
      "name": "Miki Tanoshima"
    },
    {
      "affiliations": [
        "Department of Breast and Endocrine Surgery, Tohoku University School of Medicine, Sendai, Japan"
      ],
      "name": "Narumi Harada-Shoji"
    },
    {
      "affiliations": [
        "Division of Breast Surgical Oncology, Showa Medical University School of Medicine, Tokyo, Japan"
      ],
      "name": "Kanae Taruno"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Juntendo University Graduate School of Medicine, Tokyo, Japan"
      ],
      "name": "Masami Arai"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Juntendo University Graduate School of Medicine, Tokyo, Japan",
        "Department of Breast Oncology, Juntendo University School of Medicine, Tokyo, Japan"
      ],
      "name": "Fumi Murakami"
    },
    {
      "affiliations": [
        "Ethics Support Unit/Clinical Genetics Unit, Kyoto University Hospital, Kyoto, Japan"
      ],
      "name": "Masanobu Ogawa"
    },
    {
      "affiliations": [
        "Department of Medical Genetics, Kindai University Hospital, Osaka, Japan"
      ],
      "name": "Kazuo Tamura"
    },
    {
      "affiliations": [
        "Department of Genetic Medicine, Sasaki Foundation, Kyoundo Hospital, Tokyo, Japan",
        "Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan"
      ],
      "name": "Kokichi Sugano"
    },
    {
      "affiliations": [
        "Department of Surgery, NHO Iwakuni Clinical Center, Iwakuni, Japan"
      ],
      "name": "Kohji Tanakaya"
    },
    {
      "affiliations": [
        "Department of Medical Genetics, NHO Tokyo Medical Center, Tokyo, Japan"
      ],
      "name": "Satomi Inoue"
    },
    {
      "affiliations": [
        "Department of Medical Genetics, NHO Tokyo Medical Center, Tokyo, Japan"
      ],
      "name": "Haruka Murakami"
    },
    {
      "affiliations": [
        "Department of Medical Genetics, NHO Tokyo Medical Center, Tokyo, Japan"
      ],
      "name": "Moeko Nakashima"
    },
    {
      "affiliations": [
        "Department of Medical Genetics, NHO Tokyo Medical Center, Tokyo, Japan",
        "Department of Obstetrics and Gynecology, NHO Tokyo Medical Center, Tokyo, Japan"
      ],
      "name": "Takeshi Makabe"
    },
    {
      "affiliations": [
        "Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan"
      ],
      "name": "Kenjiro Kosaki"
    },
    {
      "affiliations": [
        "Department of Breast Surgery, NHO Tokyo Medical Center, Tokyo, Japan"
      ],
      "name": "Akira Matsui"
    }
  ],
  "title": "Comprehensive evidence for the pathogenicity of the BRCA2 c.7847C>T (p.Ser2616Phe) variant specific to the Japanese population",
  "uid": "0e174eeb-40e3-5259-8c42-797f6924c6ee"
}