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

dbSNP: rs774847203

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521142	SCV000617343	pathogenic	not provided	2019-08-12	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Disrupts a critical functional domain: 20-aa repeat beta-catenin down-regulating domain, SAMP repeats/Axin binding domain, basic domain, EB1 binding domain, and hDLG binding domain (Azzopardi 2008); This variant is associated with the following publications: (PMID: 20685668, 12494469)
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	RCV003337306	SCV001585144	pathogenic	Familial adenomatous polyposis 1	2021-04-03	criteria provided, single submitter	clinical testing	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. 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 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 not present in population databases (ExAC no frequency). 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.
Myriad Genetics, Inc.	RCV003337306	SCV004045620	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.