ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467938 SCV000552499 uncertain significance Familial adenomatous polyposis 1 2018-04-16 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%). This variant has not been reported in the literature in individuals with APC-related disease. 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 affecting the intronic nucleotide at c.423-3T, results in skipping of exon 5 (PMID: 25676610). 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.
GeneDx RCV000201990 SCV000567667 uncertain significance not specified 2017-04-10 criteria provided, single submitter clinical testing This variant is denoted APC c.423-3_423-2delTA or IVS4-3_IVS4-2delTA and consists of a deletion of two nucleotides at the -3 to -2 positions in intron 4 of the APC gene. The normal sequence, with the bases that are deleted in braces, is taaaaaaaaaaaaa[ta]gGTC, where the capital letters are exonic and lowercase letters are intronic. Internal in silico models are uninformative regarding this variant's possible effect on gene splicing. APC c.423-3_423-2delTA was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. A variant denoted APC c.423-3T>A was observed in a cohort of individuals with colorectal cancer and/or polyps (Friedl 2005). Additionally, Kerr et al. (2013) reported a variant denoted APC c.423-3delT in an individual submitted for clinical genetic testing of the APC gene. While the Adenine nucleotide (a) is conserved across species, the Thymine nucleotide (t) is not conserved. Based on the currently available information, we consider APC c.423-3_423-2delTA to be a variant of uncertain significance.
Color RCV000775120 SCV000909229 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-26 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201990 SCV000256992 uncertain significance not specified no assertion criteria provided research

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