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Population Frequency of Germline BRCA1/2 Mutations
To the Editor:
Knowledge of BRCA1/2 mutation status plays an important role in multiple aspects of oncologic care.1 Inherited mutations in BRCA1/2
are highly penetrant for hereditary breast and ovarian cancer syndrome,
with lifetime risks—dependent upon the gene and population—of
50% to 70% for breast and 15% to 55% for ovarian
cancer.2 BRCA1/2 mutations also lead to increased risks of other malignancies, such as prostate, pancreatic, and male breast cancers, although
penetrance is lower.
Germline BRCA1/2 testing has traditionally been guided by personal and family cancer history1; however, two developments are changing the landscape of BRCA1/2 testing. First, the increased use of tumor genomic sequencing is leading to identification of germline BRCA1/2 mutations in patients without typical personal or family histories.3 Tumor genomic sequencing panels that contain BRCA1/2 that do not subtract matched germline DNA are fundamentally opportunistic screenings of patients with cancer. Second, for
populations with a high frequency of BRCA1/2 mutation carriers,4 screening of all individuals has been proposed.5 For consideration of population-based BRCA1/2 testing, the expected frequency of a positive result is a required piece of critical information.....Fig 1. Graphical representation of BRCA1/2 heterozygous population frequencies in Exome Variant Server (EVS) and Exome Aggregation Consortium (ExAC) databases.
Furthermore, population frequencies and penetrance estimates obtained from patients with high-risk familial hereditary breast and ovarian cancer may not be applicable in the discussion of population-based BRCA1/2 testing.
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