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.

Although the mutations listed in the table are clearly deleterious and cause breast cancer in women at very young ages, each of the kindred groups had at least one woman who carried the mutation but lived until age 80 without developing cancer. Name at least two different mechanisms (or variables) that could underlie variation in the expression of a mutant phenotype, and propose an explanation for the incomplete penetrance of this mutation. How do these mechanisms or variables relate to this explanation?

Key Concepts

BRCA1 Gene Function

The BRCA1 gene is crucial for maintaining genomic stability and repairing DNA breaks. It encodes a protein that plays a significant role in the repair of double-strand breaks through homologous recombination. Mutations in BRCA1 can lead to a loss of function, increasing the risk of breast and ovarian cancers. Understanding its normal function helps explain how mutations can lead to cancer predisposition.

Incomplete Penetrance

Incomplete penetrance refers to the phenomenon where not all individuals with a specific genotype express the expected phenotype. In the context of BRCA1 mutations, some carriers may not develop cancer due to various factors, such as environmental influences, lifestyle choices, or the presence of other genetic modifiers. This concept is essential for understanding why some individuals with deleterious mutations remain unaffected.

Modifier Genes and Environmental Factors

Modifier genes are additional genes that can influence the expression of a primary gene's phenotype, such as BRCA1. Environmental factors, including diet, exposure to carcinogens, and hormonal influences, can also play a significant role in cancer development. These factors can interact with genetic predispositions, contributing to the variability in cancer risk among individuals with the same BRCA1 mutation.