ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000022.10) (NC_000022.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
15122511 The CHEK2 Breast Cancer Case-Control Consortium (2004) analyzed the frequency of the c.1100delC variant, which results in a frameshift and loss of function, in 10 case-control studies in five counties. 10860 individuals with breast cancer and 9065 unaffected controls were genotyped. CHEK2 c.1100delC was observed in 201 cases and 64 controls for an odds ratio of 2.34 (95% CI 1.72-3.20, p = .0000001), consistent with this variant increasing breast cancer risk in women unselected for family history.
16897426 Cybulski et al (2007) studied 4454 Polish women with breast cancer and 5496 population controls. Cases were genotyped for a 5395 bp deletion affecting exons 9 and 10 of the gene and had previously been genotyped for two other loss of function variants (c.1100delC and c.444+1G>A, referred to as IVS2+1G>A). The deletion was observed in .4% of controls and 1% of unselected breast cancer cases (OR 2.2, 95% CI:1.2-4.0; p = .01). When the three loss of function variants were considered as a group they were observed in 2.3% of cases and 1.1% of controls (OR 2.2, 95% CI: 1.6 -3.0; p<.0001).
18381420 Zhang et al (2008) analyzed the frequency of c.1100delC in 3882 breast cancer patient and 8609 controls from various ancestry groups. The CHEK2 variants were observed at significant rates in the group categorized as "white", consistent with the known founder effect in the European population. The study found that white women with nonfamilial breast cancer were more likely to have a variant than controls (OR 2.6, 95% CI 1.1-5.8, p.=. 05). White women with a family history of breast cancer were enriched for CHEK2 variants compared to controls (OR 5.2, 95% CI 2.6-10.5, p < .0001).

Haploinsufficiency phenotype comments:

Truncating mutations in CHEK2 are known to increased the risk of breast, as well as an increased risk for prostate cancer (Pritchard 2016 PMID 27433846).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No evidence for dosage pathogenicity due to triplosensitivity