Work

Identification and segregation analysis of a rare germline BRCA2 frameshift variant in a Chinese family with hereditary breast and ovarian cancer

Year: 2026

Type: article

Abstract: Hereditary breast and ovarian cancer (HBOC) is primarily associated with pathogenic germline variants in BRCA1 and BRCA2 . However, the clinical interpretation of rare BRCA2 variants remains challenging when supporting evidence is limited. We report a Chinese HBOC family carrying a rare germline BRCA2 frameshift variant (c.7523_7526delGCAG) and describe the clinical and segregation evidence supporting its classification. The proband was an 81-year-old woman diagnosed with FIGO stage IIIC bilateral high-grade serous ovarian carcinoma. Postoperative matched tumor-blood multigene next-generation sequencing identified a rare heterozygous germline BRCA2 frameshift variant (c.7523_7526delGCAG). Her granddaughter, who had been diagnosed with invasive breast cancer at 37 years of age, was confirmed to harbor the same variant via targeted germline testing. Cascade Sanger testing in additional relatives identified the variant in an asymptomatic male carrier and confirmed its absence in unaffected family members, providing supporting segregation evidence. Based on sequence analysis, population database evidence, predicted loss-of-function consequence, and pedigree information, the variant was classified as likely pathogenic according to the ACMG/AMP framework. Following genetic counseling and multidisciplinary assessment, the granddaughter underwent contralateral risk-reducing mastectomy and bilateral salpingo-oophorectomy. Histopathological examination of the prophylactic resection specimens revealed benign findings. To the best of our knowledge, this is the first peer-reviewed report describing the BRCA2 c.7523_7526delGCAG variant in a Chinese HBOC family with available segregation data. This case expands the mutational spectrum and clinical documentation of rare BRCA2 frameshift variants. It also provides a useful reference for variant interpretation, genetic counseling, and risk management when the same or similar variants are encountered in clinical practice.

Source: Discover Medicine

DOI: 10.1007/s44337-026-00677-7