Heterozygous NTHL1 variant in a breast cancer survivor with malignant pleural effusion revealing metastatic colon adenocarcinoma.

NTHL1-associated tumour syndrome, linked to germline variants in the NTHL1 gene, is a rare colorectal cancer (CRC) syndrome. Initially identified in CRC cases, recent literature expanded its association to various malignancies, including breast, bladder and endometrial cancers. We present the case of a premenopausal woman with a history of left breast invasive carcinoma, treated with mastectomy, chemotherapy, radiation and endocrine therapy. Two years later, she developed new-onset dyspnoea, and further evaluation revealed a pleural effusion with pathology consistent with colonic adenocarcinoma. No primary lesions were identified on oesophagogastroduodenoscopy or colonoscopy. Genetic testing revealed an NTHL1 heterozygous variant. She was started on first-line therapy for metastatic CRC with capecitabine, oxaliplatin and bevacizumab. This case contributes to the evolving understanding of NTHL1-associated tumour syndrome, emphasising the importance of genetic evaluation in patients with multiple malignancies and the need for further research into the role of NTHL1 variants in cancer risk.