Submissions for variant NM_000038.6(APC):c.1987C>T (p.Gln663Ter)

dbSNP: rs730881240

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159538	SCV000209500	pathogenic	not provided	2014-07-08	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted APC c.1987C>T at the cDNA level and p.Gln663Ter (Q663X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through protein truncation. According to HGMD, This variant has been reported in a clinical FAP case (Konvalinka 2004) and is considered pathogenic.
Invitae	RCV002229398	SCV000552773	pathogenic	Familial adenomatous polyposis 1	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln663*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2181 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical history of colon and thyroid cancer and familial adenomatous polyposis (PMID: 15446460, 26681312). ClinVar contains an entry for this variant (Variation ID: 181792). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Myriad Genetics, Inc.	RCV002229398	SCV004043298	pathogenic	Familial adenomatous polyposis 1	2023-05-03	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.
Ambry Genetics	RCV003380497	SCV004088694	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	The p.Q663* variant (also known as c.1987C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 1987. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel whose clinical history was significant for colon cancer, thyroid cancer, and colon polyps (Susswein LR et al. Genet Med, 2016 Aug;18:823-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 2180 amino acids of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000159538	SCV004159218	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	APC: PVS1, PM2