The table in this problem summarizes some of the data that have been collected on mutations in the BRCA1 tumor-suppressor gene in families with a high incidence of both early-onset breast cancer and ovarian cancer.

Predisposing Mutations in BRCA1
Kindred    Codon    Nucleotide     Coding Effect     Frequency in
                               Change                                    Control
                                                                                Chromosomes    
 1901          24           -11 bp          Frameshift           0/180
                                                       or splice
 2082        1313         C→T           Gln→Stop            0/170
 1910        1756         Extra C        Frameshift           0/162
 2099        1775         T→G            Met→Arg            0/120
 2035         NA*          ?                  Loss of                NA*
                                                       transcript                                      _
Source: (1994). Science 266:66–71. © AAAS.

Note the coding effect of the mutation found in kindred group 2082. This results from a single base-pair substitution. Draw the normal double-stranded DNA sequence for this codon (with the 5' and 3' ends labeled), and show the sequence of events that generated this mutation, assuming that it resulted from an uncorrected mismatch event during DNA replication.

Key Concepts

BRCA1 Gene Function

The BRCA1 gene is a crucial tumor-suppressor gene that plays a significant role in maintaining genomic stability by repairing DNA breaks. Mutations in this gene can lead to an increased risk of breast and ovarian cancers, as they impair the cell's ability to fix DNA damage, allowing for the accumulation of further mutations that can drive cancer development.

Types of Mutations

Mutations can be classified into several types, including point mutations, insertions, deletions, and frameshifts. A point mutation involves a change in a single nucleotide, which can lead to a different amino acid being incorporated into a protein or a premature stop codon, potentially resulting in a nonfunctional protein. Understanding these types is essential for analyzing the effects of specific mutations on gene function.

DNA Replication and Mismatch Repair

During DNA replication, errors can occur, leading to mismatches between base pairs. The mismatch repair system is responsible for correcting these errors; however, if a mismatch is not corrected, it can result in a permanent mutation. This process is critical for understanding how mutations arise and persist in the genome, particularly in the context of cancer predisposition.