Submissions for variant NM_000038.6(APC):c.3595_3596del (p.Lys1199fs)

dbSNP: rs864622106

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002243886	SCV000259346	pathogenic	Familial adenomatous polyposis 1	2023-03-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1199Glufs*8) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1645 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 familial adenomatous polyposis (PMID: 7951218, 8162022, 11933206, 21779980). ClinVar contains an entry for this variant (Variation ID: 219466). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243886	SCV002512640	pathogenic	Familial adenomatous polyposis 1	2021-11-11	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PS4 strong, PM2, PP1 supporting
Ambry Genetics	RCV002336550	SCV002619439	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-27	criteria provided, single submitter	clinical testing	The c.3595_3596delAA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 3595 to 3596, causing a translational frameshift with a predicted alternate stop codon (p.K1199Efs*8). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1645 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 mutation has been observed in multiple individuals with a personal and/or family history that is consistent with familial adenomatous polyposis or attenuated familial adenomatous polyposis (Mandl M et al. Hum Mol Genet, 1994 Jan;3:181-4; Kohoutová M et al. Hum Mutat, 2002 Apr;19:460-1; Vandrovcová J et al. Hum Mutat, 2004 Apr;23:397; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Garzón-Benavides M et al. Rev Esp Enferm Dig, 2010 Nov;102:653-7; Jarry J et al. Fam Cancer, 2011 Dec;10:659-65; Jung SM et al. World J Gastroenterol, 2016 May;22:4380-8; Marabelli M et al. Genet Test Mol Biomarkers, 2016 12;20:777-785; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV002512065	SCV002821307	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	APC: PVS1, PP1:Strong, PM2, PS4:Supporting
Myriad Genetics, Inc.	RCV002229156	SCV004045550	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.