ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3805_3806AT[1] (p.Ile1269fs) (rs786203760)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167206 SCV000218043 pathogenic Hereditary cancer-predisposing syndrome 2014-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000202002 SCV000617339 pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing This deletion of two nucleotides in APC is denoted c.3807_3808delAT at the cDNA level and p.Ile1269MetfsX6 (I1269MfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAT[delAT]GTTT. The deletion causes a frameshift which changes an Isoleucine to a Methionine at codon 1269, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. APC Ile1269MetfsX6 has been observed in at least one individual with Familial Adenomatous Polyposis (Plawski 2008). We consider this variant to be pathogenic.
Invitae RCV000546185 SCV000647477 pathogenic Familial adenomatous polyposis 1 2018-12-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Ile1269Metfs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1575 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with familial adenomatous polyposis (PMID: 19029688). ClinVar contains an entry for this variant (Variation ID: 187473). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202002 SCV000256978 pathogenic not provided no assertion criteria provided research

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