ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1409-2_1409del

dbSNP: rs1554081631
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000524011 SCV000617333 pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing This deletion of three nucleotides in APC is denoted c.1409-2_1409delAGG at the cDNA level. The surrounding sequence is aatt[delagG]GGGA, where the capital letters are exonic and lowercase are intronic. This deletion spans the intron/exon boundary, removing the canonical splice acceptor site of intron 11. It is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one person with adenomatous polyposis, and RNA analysis suggested activation of 2 cryptic sites producing 2 aberrant transcripts that lead to premature stop codons (Kaufmann 2009). Based on currently available information, we consider APC c.1409-2_1409delAGG to be a pathogenic variant.
Invitae RCV003535806 SCV001223899 pathogenic Familial adenomatous polyposis 1 2024-01-19 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 11 of the APC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 19196998, 20685668; Invitae). ClinVar contains an entry for this variant (Variation ID: 449332). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 19196998). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002395245 SCV002697834 pathogenic Hereditary cancer-predisposing syndrome 2022-01-12 criteria provided, single submitter clinical testing The c.1409-2_1409delAGG pathogenic mutation results from a deletion of three nucleotides between positions 1409-2 and 1409 and involves the canonical splice acceptor site before coding exon 11 of the APC gene. This mutation has been identified in individuals with colonic polyposis meeting criteria for FAP or attenuated FAP (Kaufmann A et al. J Mol Diagn. 2009 Mar;11(2):131-9; Lagarde A et al. J Med Genet 2010 Oct;47(10):721-2; Ambry internal data). Upon mRNA analysis, one study confirmed aberrant splicing resulting in a transcript with a premature termination codon (Kaufmann A et al. J Mol Diagn. 2009 Mar;11(2):131-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV002527572 SCV004045325 likely pathogenic Familial adenomatous polyposis 1 2023-05-01 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.

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