NBS1 – Hereditary Breast Carcinoma

Heterozygous variants in the NBS1 gene (HGNC:7652) have been implicated as moderate-penetrance risk factors for hereditary breast carcinoma (MONDO:0016419). Nibrin, the protein encoded by NBS1, forms the MRN complex with MRE11 and RAD50, essential for DNA double-strand break recognition and repair.

In a Northern Finnish case-control cohort of 317 newly diagnosed hereditary breast cancer patients versus 1,000 matched healthy controls, the NBS1 c.448C>T (p.Leu150Phe) missense variant was identified in two unrelated probands and absent from controls (P = 0.0004) (PMID:16474176). This variant affects a conserved residue within the BRCT domain and suggests a founder effect in this population.

No familial segregation studies have been reported for c.448C>T, and no affected relatives with confirmed variant segregation have been described, yielding limited case-level evidence for pathogenicity of this allele.

Functional studies of NBS1 support a haploinsufficiency mechanism: Nbn knockout in mice is embryonic lethal, whereas hypomorphic alleles produce truncated proteins that partially rescue viability but compromise genomic stability, radiosensitivity, and cell viability (PMID:15333589). Moreover, ATM-dependent phosphorylation of nibrin at Ser343 is critical for DNA damage signaling, underscoring the impact of BRCT-domain alterations on MRN complex function (PMID:10802669).

There are no reports disputing the association of NBS1 heterozygous BRCT-domain variants with hereditary breast carcinoma, although sensitivity of risk estimates to population founder effects warrants further study.

Overall, limited genetic evidence for NBS1 c.448C>T coupled with concordant functional data supports a Limited clinical validity classification. Additional segregation and replication studies are needed to advance this association. Key take-home: NBS1 heterozygous variants involving the BRCT domain confer moderate genomic instability and may inform risk assessment in hereditary breast carcinoma.

References

• Carcinogenesis | 2006 | RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. PMID:16474176
• Human molecular genetics | 2004 | An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability. PMID:15333589
• Nature genetics | 2000 | ATM-dependent phosphorylation of nibrin in response to radiation exposure. PMID:10802669

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