ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4987G>T (p.Glu1663Ter)

dbSNP: rs758987855
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003337263 SCV002138346 pathogenic Familial adenomatous polyposis 1 2022-10-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1663*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1181 amino acid(s) of the APC protein. For these reasons, this variant has been classified as Pathogenic. 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. 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. ClinVar contains an entry for this variant (Variation ID: 236611). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002229613 SCV002511441 likely pathogenic Familial multiple polyposis syndrome 2022-04-05 criteria provided, single submitter clinical testing Variant summary: APC c.4987G>T (p.Glu1663X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory but reported in the HGMD database. The variant was absent in 250332 control chromosomes. To our knowledge, no occurrence of c.4987G>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc. RCV003337263 SCV004043395 pathogenic Familial adenomatous polyposis 1 2023-05-12 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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