ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1409-1G>T

dbSNP: rs863225313
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000202308 SCV000617334 pathogenic not provided 2017-09-12 criteria provided, single submitter clinical testing This variant is denoted APC c.1409-1G>T or IVS11-1G>T and consists of a G>T nucleotide substitutionat the -1 position of intron 11 of the APC gene. This variant destroys a canonical splice acceptor site and is predicted tocause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNAdecay or to an abnormal protein product. This variant has been reported in at least one individual with familialadenomatous polyposis (Lagarde 2010). Based on the current evidence, we consider this variant to be pathogenic
Ambry Genetics RCV000570454 SCV000675943 pathogenic Hereditary cancer-predisposing syndrome 2017-07-18 criteria provided, single submitter clinical testing The c.1409-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 11 of the APC gene. This alteration was identified in 1/863 French patients with FAP. (Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2). Another alteration at this same nucleotide positiion, c.1409-1G>A, has been reported in multiple FAP families, and it has been shown to create a new acceptor splice site one base pair downstream with a lower splicing efficiency but no indication of exon skipping (Wallis YL et al. J Med Genet. 1999 Jan;36(1):14-20; Aretz S et al. Hum Mutat. 2004 Nov;24(5):370-80). In addition to the information presented in the literature, 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 classified as pathogenic.
Invitae RCV003534477 SCV001401151 pathogenic Familial adenomatous polyposis 1 2022-07-19 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (Invitae). ClinVar contains an entry for this variant (Variation ID: 217927). Disruption of this splice site has been observed in individuals with familial adenomatous polyposis (PMID: 950360, 15459959, 19036155, 20685668; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 11 of the APC 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 APC are known to be pathogenic (PMID: 17963004, 20685668).
Myriad Genetics, Inc. RCV002519584 SCV004044867 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000202308 SCV000256920 pathogenic not provided no assertion criteria provided research

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