Family segregation study identifies a likely pathogenic BRCA2 frameshift variant in a cancer-affected lineage, highlighting the clinical utility of cascade testing for risk reduction.
Key Points
Identify and classify a rare germline BRCA2 frameshift variant in a multi-generational family affected by hereditary breast and ovarian cancer.
Matched tumor-blood multigene next-generation sequencing was conducted on an 81-year-old proband presenting with FIGO stage IIIC bilateral high-grade serous ovarian carcinoma.
Cascade Sanger sequencing was performed across affected and unaffected family members to conduct segregation analysis and evaluate pathogenicity under the ACMG/AMP framework.
Identified a rare heterozygous germline BRCA2 frameshift variant (c.7523_7526delGCAG) in the proband and her 37-year-old granddaughter with invasive breast cancer.
Segregation analysis detected the variant in an asymptomatic male relative and confirmed its absence in unaffected relatives, classifying it as likely pathogenic.
Histopathological analysis following prophylactic contralateral mastectomy and bilateral salpingo-oophorectomy in the carrier granddaughter confirmed benign tissue.