ClinVar Miner

Submissions for variant NM_000038.6(APC):c.220+2T>A (rs587781809)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130080 SCV000184907 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-09 criteria provided, single submitter clinical testing The c.220+2T>A intronic variant results from a T to A substitution two nucleotides after coding exon 2 in the APC gene. This alteration was reported in one individual undergoing clinical APC analysis. It was reported to have an allele frequency of 0.003%, and was considered to be pathogenic by the study authors; however clinical data for this individual was not provided and functional analyses were not performed in this study (Kerr SE et al. J Mol Diagn 2013 Jan; 15(1):31-43). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202191 SCV000256945 likely pathogenic not provided 2019-12-26 criteria provided, single submitter clinical testing PVS1_Mod, PM2, PP4, PP5
Invitae RCV000231290 SCV000282713 likely pathogenic Familial adenomatous polyposis 1 2020-06-22 criteria provided, single submitter clinical testing This sequence change affects a donor 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 has been observed in an individual being evaluated for familial adenomatous polyposis (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 141515). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000202191 SCV000322198 likely pathogenic not provided 2017-03-09 criteria provided, single submitter clinical testing This variant is denoted APC c.220+2T>A or IVS3+2T>A and consists of a T>A nucleotide substitution at the +2 position of intron 3 of the APC gene. This variant destroys a canonical splice donor 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 identified in an individual undergoing APC analysis and was classified as pathogenic (Kerr 2013). Based on currently available information, we consider APC c.220+2T>A to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202191 SCV000600057 pathogenic not provided 2020-03-31 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Color Health, Inc RCV000130080 SCV000686880 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503701 SCV000591018 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The APC c.220+2T>A variant was identified in HGMD, but was not identified in the literature. The variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the 5' splice consensus sequence. In addition, four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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