Submissions for variant NM_000038.6(APC):c.3880C>T (p.Gln1294Ter)

dbSNP: rs1554085373

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003742695	SCV000647481	pathogenic	Familial adenomatous polyposis 1	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1294*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1550 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 personal and/or family history of familial adenomatous polyposis (PMID: 8111410, 20685668, 20924072, 26446593). ClinVar contains an entry for this variant (Variation ID: 469942). 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.
Color Diagnostics, LLC DBA Color Health	RCV001186211	SCV001352563	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001186211	SCV002620561	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-11	criteria provided, single submitter	clinical testing	The p.Q1294* pathogenic mutation (also known as c.3880C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3880. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1550 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). This alteration has been reported in an individual with a personal and family history of familial adenomatous polyposis (FAP) (Ambry internal data). As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003335469	SCV004044660	pathogenic	Familial adenomatous polyposis 1	2023-05-09	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528293	SCV001739802	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528293	SCV001957568	pathogenic	not provided		no assertion criteria provided	clinical testing