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

dbSNP: rs758987855

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004563243	SCV002138346	pathogenic	Familial adenomatous polyposis 1	2022-10-07	criteria provided, single submitter	clinical testing	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). 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.
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.	RCV004563243	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.