Early-onset gastrointestinal malignancies may raise concerns for hereditary cancer susceptibility, although interpretation of rare germline variants identified through multigene testing remains challenging. We describe the case of a male patient diagnosed with stage IIIB mismatch repair-proficient sigmoid adenocarcinoma at age 29 who subsequently developed a poorly differentiated gastric adenocarcinoma five years later. Germline testing identified a heterozygous BLM p.E1317K variant of uncertain significance (VUS) and no other pathogenic germline alterations. Both tumors demonstrated microsatellite-stable, mismatch repair-proficient disease with low tumor mutational burden, and the patient’s family history was notable for gastric cancer in his father, collectively raising concern for an underlying cancer predisposition. Although Bloom syndrome is associated with biallelic pathogenic BLM variants, the oncologic significance of heterozygous BLM alterations remains incompletely defined. This report highlights the interpretive challenges surrounding rare germline variants in patients with multiple early-onset gastrointestinal malignancies and underscores the need for further investigation into the potential role of selected heterozygous BLM variants in cancer susceptibility.
Patel et al. (Wed,) studied this question.