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. CHEK2 has been separately curated as definitive associated with “CHEK2-related cancer predisposition” (MONDO:0700271) - Autosomal dominant inheritance, linked to Breast Cancer and Prostate Cancer. This curation focuses on refuting the association with familial ovarian cancer given that the same cancer panels are often used for assessing individuals with breast or ovarian cancer.
Given the frequency of CHEK2 variants and the cancer phenotype the curation focuses only on case-control studies for scoring genetic evidence. Several variants (mostly missense, nonsense and frameshift) that have been evaluated in case-control studies by aggregate variant analyses or single variant analyses are included in this curation. This gene-disease relationship has been studied in at least 5 case-control studies at the aggregate variant level. One large case-control published in 2016 from the The Ovarian Cancer Association Consortium (PMID 31406321 - with more than 14 thousand cases and 23 thousand controls) did not identify a significant association of pathogenic missense variants in CHEK2 and ovarian cancer. Likewise, two large case-control studies from commercial laboratories did not find significant association of pathogenic variants in CHEK2 with ovarian cancer (PMID: 31406321, 36136322). While case control studies did not support the gene-disease association, there is experimental evidence showing that CHEK2 plays an important role in DNA Damage Response, and other genes in this pathway (such as ATM) are known ovarian cancer predisposing genes (0.5 point, PMID: 10673500).
In summary, given the lack of significant association in several large ovarian cancer case-control studies to date, the evidence supporting the relationship between CHEK2 and autosomal dominant hereditary ovarian carcinoma has been refuted and no valid evidence remains to support the claim. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP in 2016. 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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