Submissions for variant NM_000038.6(APC):c.3904del (p.Leu1302fs)

dbSNP: rs1064794042

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484665	SCV000567661	pathogenic	not provided	2015-08-19	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in APC is denoted c.3904delC at the cDNA level and p.Leu1302CysfsX3 (L1302CfsX3) at the protein level. The normal sequence, with the base that is deleted in braces, is TACC[C]TGCA. The deletion causes a frameshift, which changes a Leucine to a Cysteine at codon 1302, and creates a premature stop codon at position 3 of the new reading frame. Even though this frameshift occurs in the last exon of the gene, it is significant since the last 1542 correct amino acids are replaced by 2 incorrect ones. This variant is predicted to cause loss of normal protein function through protein truncation. APC c.3904delC has been observed in at least two individuals with Familial Adenomatous Polyposis (Lagarde 2010). we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004564170	SCV002227839	pathogenic	Familial adenomatous polyposis 1	2021-02-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1302Cysfs*3) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1542 amino acid(s) of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 20685668). ClinVar contains an entry for this variant (Variation ID: 419687). 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.
Myriad Genetics, Inc.	RCV004564170	SCV004043820	pathogenic	Familial adenomatous polyposis 1	2023-05-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.