Submissions for variant NM_000038.6(APC):c.2004del (p.His668_Leu669insTer)

dbSNP: rs587782303

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131187	SCV000186136	pathogenic	Hereditary cancer-predisposing syndrome	2013-02-28	criteria provided, single submitter	clinical testing	This alteration occurs at the 3' terminus of the APC gene and is not expected to trigger nonsense-mediated mRNA decay. 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000211899	SCV000209569	pathogenic	not provided	2015-03-10	criteria provided, single submitter	clinical testing	This deletion of one nucleotide is denoted c.2004delC at the cDNA level and p.Leu669Ter (L669X) at the protein level. The normal sequence, with the base that is deleted in brackets, is AACA[C]TTAA. The deletion creates a nonsense variant, changing a Leucine to a premature stop codon. This variant is predicted to cause loss of normal protein function through protein truncation. APC Leu669Ter, has been observed in two families reported to have a phenotype consistent with attenuated FAP (Cragun 2014, Castellsagne 2010).
Invitae	RCV003650397	SCV000253728	pathogenic	Familial adenomatous polyposis 1	2021-11-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the APC protein in which other variant(s) (p.Gln1062*) have been determined to be pathogenic (PMID: 1316610, 8162022, 15771908). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 142199). This premature translational stop signal has been observed in individual(s) with colorectal cancer and polyps and/or familial adenomatous polyposis (PMID: 1316610, 8162022, 15771908, 24506336, 26681312). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu669*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2175 amino acid(s) of the APC protein.
Myriad Genetics, Inc.	RCV003335122	SCV004044873	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.