SLX4

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013499

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

*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).

Inheritance Pattern: AR

Disease ID:MONDO:0013499

Submitter: G2P

Inheritance Pattern: Unknown

Disease ID:MONDO:0016248

Submitter: ClinGen

Inheritance Pattern: AR

Disease ID:MONDO:0013499

Submitter: ClinGen

*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. SLX4 was first reported in relation to autosomal recessive inheritance and Fanconi anemia complementation group P in 2011 (Kim Y et al., PMID: 21240275; Stoepker C et al., PMID: 21240277). Fanconi anemia is a rare hereditary disease characterized by genomic instability, developmental abnormalities, bone marrow failure and cancer predisposition, mainly leukemia and solid tumors. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split autosomal dominant hereditary breast cancer into separate curations due to phenotypic variability and different inheritance patterns. Therefore, this curation solely focuses on autosomal recessive FANCP. The mechanism of pathogenicity is loss of function. Ten variants (including nonsense, frameshift, and intronic) that have been reported in six probands in three publications (PMIDs: 21240275, 21240277, 36463940) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 Points) has been reached. This gene-disease relationship is also supported by experimental evidence from animal and cell models (3 Points, PMID 21240275, 21240276). Mice with knockout of Btbd12, the mouse ortholog of SLX4, recapitulated many key features of the human Fanconi anemia, for example Btbd12-deficient animals were born at sub-Mendelian ratios, had greatly reduced fertility, were developmentally compromised and were prone to blood cytopenias. In addition, although expression of wildtype SLX4 fully rescued the FA phenotypes in fibroblasts derived from FA patients carrying biallelic SLX4 variants, mutant SLX4 proteins failed to rescue these phenotypes. In summary, there is definitive evidence supporting the relationship between SLX4 and autosomal recessive inheritance Fanconi anemia, complementation group P. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Hereditary Cancer GCEP on the meeting date of October 27, 2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0013499

Submitter: PanelApp Australia