CHEK2 – Hereditary Nonpolyposis Colon Cancer

CHEK2 heterozygous truncating variants have been identified opportunistically in individuals with hereditary nonpolyposis colorectal cancer (HNPCC) suspicion. Opportunistic testing of 205 HNPCC-suspected probands revealed 2 carriers of CHEK2 pathogenic variants in mismatch repair–proficient colorectal tumors ([PMID:30927264]). In a Spanish hereditary cancer cohort, (likely)-pathogenic CHEK2 variants were detected in 1.0% ([PMID:32906215]) of patients meeting HNPCC clinical criteria. No multi-generational segregation data or recurrent founder alleles have been reported in colorectal cancer families.

CHEK2 encodes a checkpoint kinase essential for DNA damage–induced cell cycle arrest and apoptosis. Drosophila chk2 mutants exhibit complete loss of DNA damage–induced apoptosis and partial checkpoint arrest ([PMID:11728459]), consistent with haploinsufficiency. Functional analysis of the frameshift allele c.1100del (p.Thr367MetfsTer15) demonstrates reduced protein stability and kinase activity ([PMID:15818573]). However, homozygosity for CHEK2*1100delC did not produce a severe colorectal phenotype, indicating incomplete penetrance in colon cancer predisposition. Overall, existing data support a limited role for CHEK2 variants in HNPCC.

Key Take-home: CHEK2 pathogenic variants confer a modest, incompletely penetrant risk for hereditary nonpolyposis colon cancer; testing may be considered in MMR-proficient families.

References

• International journal of cancer • 2019 • Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels. PMID:30927264
• Human mutation • 2020 • Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients. PMID:32906215
• The Journal of pathology • 2005 • Homozygosity for a CHEK2*1100delC mutation identified in familial colorectal cancer does not lead to a severe clinical phenotype. PMID:15818573
• FEBS letters • 2001 • Drosophila Chk2 is required for DNA damage-mediated cell cycle arrest and apoptosis. PMID:11728459

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