ClinVar Miner

Submissions for variant NM_000038.6(APC):c.423-3_423-2del (rs863225354)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467938 SCV000552499 likely pathogenic Familial adenomatous polyposis 1 2020-10-19 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 an intronic nucleotide at c.423-3T within the consensus splice site of the intron. This variant is present in population databases (rs762269434, ExAC 0.009%). Variants affecting the c.423-3T intronic nucleotide have 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: 217982). 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. In addition, experimental studies using patient RNA have shown that a different variant (c.423-4_423-2delATA) similarly affects the intronic nucleotide at c.423-3T, results in skipping of exon 5 (PMID: 25676610). 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 RCV001705159 SCV000567667 likely pathogenic not provided 2020-01-27 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In-silico analysis is inconclusive as to whether the variant alters gene splicing; This variant is associated with the following publications: (PMID: 23159591, 20223039, 28051113, 28152038)
Color Health, Inc RCV000775120 SCV000909229 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000775120 SCV001183798 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-12 criteria provided, single submitter clinical testing The c.423-3_423-2delTA intronic variant, located in intron 3 of the APC gene, results from a deletion of two nucleotides within intron 3 of the APC gene, including the canonical splice acceptor site. Though this exact alteration has not been reported in the literature, another alteration (c.423-3T>A) which similarly affects the native acceptor site 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). Additionally, this alteration has been detected in an individual with polyposis (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The BDGP and ESEfinder splice site prediction tools do not 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000201990 SCV000256992 uncertain significance not specified no assertion criteria provided research

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