SLX4 encodes a protein that functions as a scaffold element for the assembly of a multiprotein complex containing endonucleases activity required for repair of specific types of DNA lesions and critical for cellular responses to replication fork failure. Biallelic SLX4 mutations are associated with Fanconi anemia, complementation group P. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, curations to refute or dispute can be split when needed. We only focus on hereditary breast cancer in this curation. Evidence curated in this gene-disease relationship includes case-control data and experimental data.
Summary of Case-Control Data: 0 point This gene-disease relationship has been studied in at least 2 case-control or meta-analysis studies at the aggregate variant level. In 2021, a large case-control study [CARRIERS (PMID: 33471974) with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in SLX4 and breast cancer. Another meta-analysis study (PMID: 32488392) with smaller populations also did not show an association of SLX4 variants with breast cancer.
Summary of Experimental Data: 0.25 points While case control studies did not support the gene-disease association, Hodskinson et al. showed that mice with homozygous SLX4 knockout developed epithelial cancers, suggesting the role as a tumor suppressor (PMID: 24726326).
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 SLX4 and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as limited by the Breast/Ovarian Cancer GCEP on 3/8//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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