This study investigates the mutational evolution of a lobular breast tumor at single nucleotide resolution. The researchers sequenced the genomes and transcriptomes of an estrogen receptor-positive metastatic lobular breast cancer, identifying 32 somatic non-synonymous coding mutations in the metastasis. They also measured the frequency of these mutations in the primary tumor, which had been diagnosed 9 years earlier. Five mutations were prevalent in the primary tumor, six were present at lower frequencies, 19 were not detected, and two were undetermined. The analysis revealed two new RNA-editing events affecting SRP9 and COG3. The findings highlight that single nucleotide mutational heterogeneity can be a property of low or intermediate-grade primary breast cancers and that significant evolution can occur during disease progression. The study emphasizes the importance of sequencing both primary and metastatic tumors to understand the genomic landscape of breast cancer.This study investigates the mutational evolution of a lobular breast tumor at single nucleotide resolution. The researchers sequenced the genomes and transcriptomes of an estrogen receptor-positive metastatic lobular breast cancer, identifying 32 somatic non-synonymous coding mutations in the metastasis. They also measured the frequency of these mutations in the primary tumor, which had been diagnosed 9 years earlier. Five mutations were prevalent in the primary tumor, six were present at lower frequencies, 19 were not detected, and two were undetermined. The analysis revealed two new RNA-editing events affecting SRP9 and COG3. The findings highlight that single nucleotide mutational heterogeneity can be a property of low or intermediate-grade primary breast cancers and that significant evolution can occur during disease progression. The study emphasizes the importance of sequencing both primary and metastatic tumors to understand the genomic landscape of breast cancer.