CHEK2 gene encodes for the CHK2 serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks, through the ATM-CHK2-p53 DNA damage response pathway. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) and inheritance pattern for Breast Cancer and Prostate Cancer, which were lumped into the disease entity “CHEK2-related cancer predisposition” (MONDO:0700271) - Autosomal dominant inheritance. The split curation for Ovarian Carcinoma (refuted) has been curated separately. CHEK2 results in low to moderate penetrance for cancer, for which multiple published studies study different cancer types, ranging from single case reports to large case-control analyses[SP1] . In addition to breast and prostate cancer, there is limited evidence for renal, pancreatic, thyroid and gastric carcinoma, for which larger studies are needed (PMID 37490054). The common truncating CHEK2 variant (c.1100del) has been demonstrated to convey colorectal cancer (PMID: 12690581) .
Given the frequency of CHEK2 variants and the cancer phenotype the curation focuses only on breast and prostate cancer case-control studies for scoring genetic evidence. 8 variants (missense, nonsense and frameshift) evaluated in case-control studies by aggregate variant analyses or single variant analyses are included in this curation (PMIDs 27595995, 33471974, 33471991). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. The gene-disease relationship is also supported by experimental evidence (animal models, expression studies and in vitro functional assays) (PMIDs: 12094328, 20434834, 19805189, 34903604). In summary, there is definitive evidence supporting the relationship between CHEK2 and autosomal dominant CHEK2-related cancer predisposition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This re-curation was approved by the ClinGen Hereditary Cancer GCEP on 09/27/2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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