Submissions for variant NM_005359.6(SMAD4):c.250-2A>G

dbSNP: rs1555685142

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578818	SCV000680991	likely pathogenic	not provided	2017-06-30	criteria provided, single submitter	clinical testing	Although the c.250-2 A>G variant in the SMAD4 gene has not been reported as a pathogenic or benign to ourknowledge, it destroys the canonical splice acceptor site in intron 2 and is predicted to cause abnormal gene splicing.Other splice site variants in the SMAD4 gene have been reported in the Human Gene Mutation Database inassociation with JPS (Stenson et al., 2014). Furthermore, the c.250-2 A>G variant is not observed in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).In summary, c.250-2 A>G in the SMAD4 gene is interpreted as a likely pathogenic variant
Labcorp Genetics (formerly Invitae), Labcorp	RCV002529046	SCV003232720	likely pathogenic	Juvenile polyposis syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the SMAD4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SMAD4 are known to be pathogenic (PMID: 16152648, 16436638, 22810475). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 489018). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV004024594	SCV004931968	likely pathogenic	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2024-02-09	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.