ClinVar Miner

Submissions for variant NM_000038.6(APC):c.221-2A>G (rs786201291)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163246 SCV000213773 pathogenic Hereditary cancer-predisposing syndrome 2017-11-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other strong data supporting pathogenic classification
Color RCV000163246 SCV000903450 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000480238 SCV000566884 pathogenic not provided 2017-08-25 criteria provided, single submitter clinical testing This pathogenic variant is denoted APC c.221-2A>G or IVS3-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 3 of the APC gene. The variant destroys a canonical splice acceptor site and 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 two individuals undergoing evaluation for Familial Adenomatous Polyposis and in one woman with a personal history of early-onset colorectal cancer and multiple adenomas and a family history of duodenal and early-onset colorectal cancer (Beaton 2008, Kerr 2013). Based on the current evidence, we consider APC c.221-2A>G to be pathogenic.
Invitae RCV000476651 SCV000552586 likely pathogenic Familial adenomatous polyposis 1 2018-12-06 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the APC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with familial adenomatous polyposis (FAP) (PMID: 18629394, 23159591). ClinVar contains an entry for this variant (Variation ID: 184117). Donor and acceptor splice site variants 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). 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.

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