ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3920_3924del (p.Ile1307fs) (rs1064794229)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485674 SCV000568277 pathogenic not provided 2018-05-24 criteria provided, single submitter clinical testing This deletion of five nucleotides in APC is denoted c.3920_3924delTAAAA at the cDNA level and p.Ile1307ArgfsX6 (I1307RfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAAA[delTAAAA]GAAA. The deletion causes a frameshift which changes an Isoleucine to an Arginine at codon 1307, and creates a premature stop codon at position 6 of the new reading frame. Even though this frameshift occurs in the second to last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 1537 amino acids are replaced by five incorrect amino acids. This variant is predicted to cause loss of normal protein function through protein truncation. APC c.3920_3924delTAAAA has been reported in two individuals for whom clinical APC testing was ordered (Kerr 2013). Based on the currently available information, we consider this deletion to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501734 SCV000591160 uncertain significance not specified 2015-03-27 criteria provided, single submitter clinical testing
Invitae RCV000821757 SCV000962526 pathogenic Familial adenomatous polyposis 1 2018-12-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Ile1307Argfs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1537 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals who underwent APC genetic testing (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 419999). This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease For these reasons, this variant has been classified as Pathogenic.

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