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• Nucleotide usage in EGFR gene is biased towards codons ending with C. • Germline mutations have preferable directions: C to T and G to A. • Somatic mutations in cancer cells have preferable directions: C to T and G to A. • There is positive selection of amino acid replacements in cancer cells. • Nonsense mutations are neutral in cancer cells. In this study we investigated nucleotide usage biases along the length of a gene encoding human epidermal growth factor receptor (EGFR) and found out that there had been mutational GC-pressure with stronger asymmetric C-pressure in that gene before the preferable direction of nucleotide mutations changed. Current preferable direction of germline mutations in EGFR gene has been estimated with the help of Ensembl data base of gene variations. Preferable direction of somatic mutations in EGFR gene from cancer cells has been estimated with the help of COSMIC data base. Both germline and somatic mutations in cancer cells have the same GC to AT preferable direction in EGFR gene. These data have been used with the aim to find fragments of EGFR gene that have lower probability of missense C to T and G to A transitions to occur. So, the less mutable parts of extracellular EGFR domain are: C-terminal part of the first beta barrel and the central part of the second beta barrel. The less mutable parts of tyrosine kinase EGFR domain are: ATP-binding site (partially), regulatory alpha helix, and fragments that change their secondary structure during the activation process. These parts of EGFR should be considered as the best targets for new types of therapy development. Such criterion as low mutability is especially important for the selection of targets for anti-tumor therapy, since we have detected positive selection of amino acid replacements during somatic mutagenesis of EGFR gene in cancer cells. [ABSTRACT FROM AUTHOR]