Muir‐Torre syndrome is defined by the development of sebaceous skin lesions in individuals who carry a germline mismatch repair (MMR) gene mutation. Loss of expression of MMR proteins is frequently observed in sebaceous skin lesions, but MMR‐deficiency alone is not diagnostic for carrying a germline MMR gene mutation. Whole exome sequencing was performed on three MMR‐deficient sebaceous lesions from individuals with MSH2 gene mutations (Lynch syndrome) and three MMR‐proficient sebaceous lesions from individuals without Lynch syndrome with the aim of characterizing the tumor mutational signatures, somatic mutation burden, and microsatellite instability status. Thirty predefined somatic mutational signatures were calculated for each lesion. Signature 1 was ubiquitous across the six lesions tested. Signatures 6 and 15, associated with defective DNA MMR, were significantly more prevalent in the MMR‐deficient lesions from the MSH2 carriers compared with the MMR‐proficient non‐Lynch sebaceous lesions (mean ± SD=41.0 ± 8.2% vs. 2.3 ± 4.0%, p = 0.0018). Tumor mutation burden was, on average, significantly higher in the MMR‐deficient lesions compared with the MMR‐proficient lesions (23.3 ± 11.4 vs. 1.8 ± 0.8 mutations/Mb, p = 0.03). All four sebaceous lesions observed in sun exposed areas of the body demonstrated signature 7 related to ultraviolet light exposure. Tumor mutational signatures 6 and 15 and somatic mutation burden were effective in differentiating Lynch‐related from non‐Lynch sebaceous lesions.