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A single patient with tibial osteosarcoma developed synchronous pulmonary and skeletal muscle metastases; targeted sequencing of an 806-gene cancer panel identified a heterozygous germline BLM missense variant c.1021C>T (p.Leu341Phe) ([PMID:35057767]). No additional unrelated cases or familial segregation data have been reported, and in silico tools predict this variant as tolerated. Functional studies of BLM in Bloom syndrome underscore its role in maintaining genome stability, but no osteosarcoma-specific assays or animal models have been undertaken to date, leaving the pathogenicity in this context unproven. To date, evidence is limited to a single proband, without supportive segregation or tumor functional validation. Additional cohort analyses and experimental modeling are needed to establish BLM as a bona fide osteosarcoma predisposition gene.
Key Take-home: BLM c.1021C>T (p.Leu341Phe) has been observed once in an osteosarcoma with rare extrapulmonary metastases, but current data are insufficient for clinical genetic testing for osteosarcoma risk.
Gene–Disease AssociationLimitedSingle proband with germline BLM c.1021C>T (p.Leu341Phe) in osteosarcoma ([PMID:35057767]) Genetic EvidenceLimitedOne missense variant in a single case, no segregation or additional probands Functional EvidenceLimitedNo osteosarcoma-specific functional assays or models validating BLM variant |