ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4831C>T (p.Gln1611Ter) (rs774847203)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521142 SCV000617343 pathogenic not provided 2018-01-16 criteria provided, single submitter clinical testing This variant is denoted APC c.4831C>T at the cDNA level and p.Gln1611Ter (Q1611X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through protein truncation. This variant has been reported in at least one individual with familial adenomatous polyposis (Lagarde 2010) and is considered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780834 SCV000918434 likely pathogenic Familial multiple polyposis syndrome 2018-03-23 criteria provided, single submitter clinical testing Variant summary: APC c.4831C>T (p.Gln1611X) 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. The variant was absent in 246062 control chromosomes. c.4831C>T has been reported in the literature in an individual affected with Familial Adenomatous Polyposis (Lagarde 2010). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. 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.
Invitae RCV001385325 SCV001585144 pathogenic Familial adenomatous polyposis 1 2020-03-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Gln1611*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1233 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial adenomatous polyposis (PMID: 20685668, 14961559). This variant is also known as 3982C>T (Q1328X) in the literature. ClinVar contains an entry for this variant (Variation ID: 449336). 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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