Submissions for variant NM_000038.6(APC):c.5978del (p.Pro1993fs)

dbSNP: rs1554087123

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003535795	SCV001585145	pathogenic	Familial adenomatous polyposis 1	2022-02-06	criteria provided, single submitter	clinical testing	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. 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: 433672). This premature translational stop signal has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 20223039). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1993Leufs*51) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 851 amino acid(s) of the APC protein.
Myriad Genetics, Inc.	RCV002524131	SCV004045292	pathogenic	Familial adenomatous polyposis 1	2023-05-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501056	SCV000591194	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Pro1993LeufsX51 deletion was not previously identified in the literature nor by our laboratory. This deletion is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1993 and leads to a premature stop codon 51 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis. In summary based on the above information, this deletion is classified as pathogenic.