CHEK2 – Hereditary Breast Carcinoma

Checkpoint kinase 2 (CHEK2) is a pivotal transducer of the ATM-mediated DNA damage response, phosphorylating downstream effectors to induce cell-cycle arrest and apoptosis. Germline CHEK2 variants have been repeatedly identified in families with hereditary breast carcinoma (Hereditary Breast Carcinoma).

Genetic Evidence (Autosomal dominant): truncating variant c.1100del (p.Thr367MetfsTer15) was found in 27/237 probands (11.4%) and at least one carrier in 15/71 non-BRCA1/2 multiple-case families (PMID:14678969); the missense variant c.470T>C (p.Ile157Thr) occurs in 77/1 035 (7.4%) unselected breast cancer patients versus 100/1 885 (5.3%) controls (PMID:15239132). Independent segregation has been demonstrated in 2 families (PMID:15095295).

Variant Spectrum: both loss-of-function (frameshift, splice) and deleterious missense alleles cluster in the Forkhead-associated domain. Founder risk allele c.1100del (p.Thr367MetfsTer15) recurs in European populations, and c.470T>C (p.Ile157Thr) shows moderate penetrance.

Functional Evidence: CHEK2 mutants fail to undergo ATM-dependent Thr68 phosphorylation and oligomerization, leading to reduced kinase activity against targets such as BRCA1 (PMID:16982735). Drosophila chk2 null models show defective DNA damage-induced arrest and apoptosis, underscoring conserved checkpoint function (PMID:11728459).

Conflicting Data: German cohorts reported low prevalence and incomplete segregation of c.1100del, suggesting population-specific risk estimates (PMID:15095295).

Integration & Clinical Utility: The convergence of case-control, segregation and mechanistic studies supports a strong association between heterozygous CHEK2 variants and hereditary breast carcinoma. Testing for c.1100del and other deleterious alleles informs risk stratification and management in BRCA-negative families.

Key take-home: Germline CHEK2 testing enables tailored surveillance and risk reduction in hereditary breast carcinoma.

References

• Cancer research • 2003 • The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. PMID:14678969
• International journal of cancer • 2004 • CHEK2 variant I157T may be associated with increased breast cancer risk. PMID:15239132
• International journal of cancer • 2004 • Limited relevance of the CHEK2 gene in hereditary breast cancer. PMID:15095295
• FEBS letters • 2001 • Drosophila Chk2 is required for DNA damage-mediated cell cycle arrest and apoptosis. PMID:11728459
• Cancer research • 2006 • Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation. PMID:16982735

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