BLM – Breast Cancer

Heterozygous carriers of the BLM founder nonsense variant c.1642C>T (p.Gln548Ter) were initially reported in 17/1,498 (1.1%) unselected breast cancer cases versus 2/1,093 (0.2%) controls (p = 0.004) (PMID:21815139). A subsequent meta-analysis of four case–control series corroborated a significant association (Mantel–Haenszel OR 5.1, 95% CI 1.2–21.9, p = 0.03) for p.Gln548Ter carriers (PMID:23225144).

However, a large study of 14,804 unselected cases and 4,698 controls detected the BLM founder allele in 0.55% of both groups (82/14,804 vs. 26/4,698; OR 1.0, 95% CI 0.6–1.6) and found no differences in tumor characteristics or loss of heterozygosity among carriers (PMID:31614901). In a cohort of 5,391 affected women, BLM variants were observed only in combination with BRCA1 or CHEK2 mutations, without independent risk or earlier onset, and with rare somatic loss of the wild-type allele (PMID:24800916).

Experimental data delineate BLM’s key roles in DNA replication-fork restart, homologous recombination suppression, and genomic stability in homozygous Bloom syndrome patients, but these mechanistic insights have not been extended to heterozygous variant carriers in a breast cancer context.

Taken together, initial small studies suggested a modest risk conferred by BLM p.Gln548Ter, yet larger, well-powered cohorts refute this association. The overall evidence is therefore conflicting, and current data do not support BLM as a stand-alone autosomal dominant breast cancer susceptibility gene.

Key Take-home: Despite early reports of founder variant enrichment, robust large-scale data demonstrate no significant predisposition to breast cancer in heterozygous BLM p.Gln548Ter carriers, and BLM testing is not indicated for routine breast cancer risk assessment.

References

• International Journal of Cancer • 2012 • High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia. PMID:21815139
• Human Mutation • 2013 • Bloom’s syndrome-causing missense mutations in human DNA helicase disorders. PMID:23276657
• Cancers • 2019 • Inherited Variants in BLM and the Risk and Clinical Characteristics of Breast Cancer. PMID:31614901
• Breast Cancer Research and Treatment • 2014 • Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations. PMID:24800916

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