SEMA4 encodes Semaphorin 4A, a single-pass type I membrane protein involved in axon guidance, morphogenesis, carcinogenesis, and immunomodulation. Although there is no disease associated with SEMA4 in OMIM, there was an early assertion of association with Lynch syndrome (Schulz et al. PMID: 25307848). This curation will focus on this disorder. In 2014, Schulz and co-workers first proposed the association of germline SEMA4 variants in autosomal dominant Lynch syndrome by reporting a missense variant (splice site and missense) in a family with Lynch syndrome. This study also found that this variant is associated with colorectal cancer by a case-control analysis. However, in 2016, Kinnersley et al reported a well-powered study showing no statistical significance between this variant and colorectal cancer. The pedigree from the family with colorectal cancer also showed incomplete segregation. Hence Kinnersley et al concluded that there is an issue of type 1 error in Schulz et al. paper. Considering the lack of substantial association in genetic and experimental studies, the Hereditary Cancer GCEP has disputed this gene-disease association. More evidence is needed to either support or entirely refute the role SEMA4A plays in autosomal dominant Lynch syndrome. This gene-disease pair was originally evaluated as limited by the Colon Cancer GCEP on 11/13/2017. This re-curation was approved by the ClinGen Hereditary Cancer GCEP on 3/22/2024 (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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