ClinVar Miner

Submissions for variant NM_000038.6(APC):c.423-4_423-2del

dbSNP: rs876657408
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003651887 SCV000552734 uncertain significance Familial adenomatous polyposis 1 2023-11-07 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with APC-related conditions (PMID: 25676610). ClinVar contains an entry for this variant (Variation ID: 411534). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5 and introduces a premature termination codon (PMID: 25676610). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Ambry Genetics RCV003298503 SCV004001059 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter clinical testing The c.423-4_423-2delATA intronic variant, located in intron 3 of the APC gene, results from a deletion of 3 nucleotides within intron 3 of the APC gene. This alteration has been reported in the literature in a family affected with Cenani-Lenz syndrome (Patel N et al. J Med Genet, 2015 May;52:317-21; Maddirevula S et al. Genet Med, 2018 Dec;20:1609-1616). Although these nucleotides are located near a canonical splice site, the canonical splice acceptor "ag" sequence is preserved. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data; Patel N et al. J Med Genet, 2015 May;52:317-21; Maddirevula S et al. Genome Biol, 2020 Jun;21:145). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
OMIM RCV000185617 SCV000238529 uncertain significance not provided 2015-05-01 no assertion criteria provided literature only

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