ClinVar Miner

Submissions for variant NM_000038.6(APC):c.423-3T>A (rs587782293)

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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 RCV000131175 SCV000186122 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-29 criteria provided, single submitter clinical testing The c.423-3T>A intronic variant results from a T to A substitution 3 nucleotides upstream from coding exon 4 in the APC gene. This variant has been detected in multiple individuals with a clinical diagnosis of FAP or AFAP. (Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Ambry internal data). In another study, this variant was detected in 1/1591 consecutive individuals undergoing gene sequencing for APC. The authors of this study classified this variant as likely pathogenic based on results of in silico splice prediction tools (Kerr SE et al. J Mol Diagn. 2013;15(1):31-43). This nucleotide position is poorly conserved in available vertebrate species. Neither the BDGP nor ESEfinder splice prediction software could produce a reliable prediction for the nearby native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000686573 SCV000814096 uncertain significance Familial adenomatous polyposis 1 2019-07-27 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with typical or attenuated FAP and individuals undergoing APC testing (PMID: 20223039, 23159591, Invitae). ClinVar contains an entry for this variant (Variation ID: 142189). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000131175 SCV000905871 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing
Mendelics RCV000686573 SCV001136873 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001353717 SCV001714738 uncertain significance not provided 2019-05-14 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202091 SCV000256993 uncertain significance not specified no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353717 SCV000591027 uncertain significance not provided no assertion criteria provided clinical testing The APC c.423-3T>A variant was identified in 1 of 2332 proband chromosomes (frequency: 0.0004) from German individuals or families with FAP (Friedl 2005). The variant was identified in the ClinVar database with conflicting classifications. Ambry Genetics classified it as likely pathogenic and the Mayo Clinic Testing Laboratories as of uncertain significance. The InSight Colon Cancer Database identified it 1x with no classification and it was identified in the LOVD database 2x as having splicing effect. The c.423-3T>A variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database, COSMIC, “Zhejiang Colon Cancer Database”, GeneInsight COGR database, MutDB or UMD. The c.423-3T>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% chance of the loss of the splice acceptor site, and 1 of 5 of the above programs predict a greater than 10% chance that this variant alters a cryptic splice donor site. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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