Efficient DNA repair, DNA replication, and regulating cell cycle checkpoints are all essential factors in protection from genomic instability. Breast cancer 2 (Brca2) and partner and localizer of BRCA2 (Palb2) are well-known factors associated with increased risk of breast and ovarian cancers. They both have essential roles involved in DNA repair, protection of stalled replication forks, and maintenance of the cell cycle checkpoint. While these two proteins interact and have similar roles in protection of the genome, what hasn’t been shown is if the interaction is critical for full functionality in vivo. BRCA2 and PALB2 each have their own DNA binding motifs and both can bind to RAD51, so can the protection of the genome occur even if this interaction is perturbed? To investigate the functional importance of the interaction between BRCA2 and PALB2 we created a knock-in mouse model of BRCA2. The single amino acid change (Gly25Arg) is in the highly conserved N-terminal region that interacts with PALB2. This particular mutation was previously shown to cause a decrease but not abolish this interaction. These mice vary in phenotype and tumor latency base on whether the mutation is in homozygous or hemizygous state. An additional heterozygous loss of Palb2Gt(CG0691)Wtsi results in earlier tumor formation and more severe phenotypes in the mice. At the cellular level there is an increasing amount of genomic instability with the decreasing amount of interaction between BRCA2 and PALB2. This also holds true when looking at the ability of RAD51 foci formation after damage and the protection of the DNA replication fork in times of replication stress. This series of phenotypically distinct mouse models shows the critical need for proper interaction between these two genes for protection of the genome. In addition this series of animal models will also distinguish between the protection of the replication fork verses the ability for efficient HR in terms of being able to protect against genomic instability.