GEN1 encodes an endonuclease that is involved in resolution of Holliday junctions during homologous recombination and double-strand break repair. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is no disease associated with GEN1 in OMIM, and curations to refute or dispute can be split when needed.
Summary of Case-Control Data: 0 point This gene-disease relationship has been studied in at least 2 case-control studies at the aggregate or single variant level. In 2021, a large case-control study [BCAC (PMID: 33471991); with more than 48 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in GEN1 and breast cancer. In addition, another case-control study (PMID: 20512659) with smaller populations did not show an association of GEN1 variants with breast cancer.
Summary of Experimental Data: 1.25 point While case control studies did not support the gene-disease association, there is experimental evidence suggesting the function as a Holliday junction-resolving endonuclease (PMID: 19020614). Wyatt et al. showed that cells depleted of GEN1 exhibited defects in chromosome segregation and anaphase bridge formation after DNA damage (PMID: 24076221). GEN1 depletion also showed aberrant centrosome numbers and formation of multiple spindle poles during mitosis (PMID: 23166748). In addition, Sun et al. demonstrated that GEN1 expression is correlated with mammary epithelial cell proliferation and differentiation in various physiological stages (PMID: 24980922).
Overall Summary: In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between GEN1 and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 12/13/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 6/9/2023 (SOP Version 9).
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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