Despite the tremendous global effort in discovering and cataloguing somatic mutations in cancer-related genes and the impact they exert on human cancers, the effects of these mutations on the protein expression levels are inadequately addressed. Here, we evaluated the expression of proteins represented by the Ion AmpliSeq™ Cancer Hotspot Panel v2 and cell markers, in human breast and kidney tumor-normal adjacent samples. To this end, we employed two distinct proteomic techniques—Reverse Phase Protein Array (RPPA) and Liquid Chromatography-Mass Spectrometry (LC-MS). The latter was used in progressively advanced modes: data-dependent acquisition, data-independent acquisition, and parallel reaction monitoring, aiming to improve the quantitation of specific protein expression levels. Significant alterations in protein expression were observed using both methods, also revealing patient-specific proteomic profiles. Furthermore, both overlapping and unique findings between RPPA and LC-MS were observed, indicating their complementary nature. However, Spearman coefficient analysis demonstrated varying degrees of correlation between RPPA and LC-MS data. This integrated approach underscores the necessity of dual-platform analyses in cancer proteomics to improve diagnostic and therapeutic strategies. Our study aims to fill the gap in assessing the proteomic consequences of somatic mutations, suggesting a potential need for confirmation that a cancer related protein is up- or downregulated -and to what extent- by both RPPA and LC-MS to ensure robust and reliable findings.