Submissions for variant NM_000038.6(APC):c.5490_5493del (p.Asn1830fs)

dbSNP: rs730881273

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497264	SCV000209571	pathogenic	not provided	2023-04-25	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1316610, 20434453, 11247896, 27081525, 22135120, 9824584, 17293347, 8381579, 28569743, 8940264, 15311282, 23159591, 26681312)
Invitae	RCV000234000	SCV000282780	pathogenic	Familial adenomatous polyposis 1	2016-02-04	criteria provided, single submitter	clinical testing	This sequence change deletes 4 nucleotides from exon 16 of the APC mRNA (c.5490_5493delTGAA), causing a frameshift at codon 1830. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Asn1830Lysfs*32). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated APC protein by eliminating ~1000 amino acid residues (~36%) from the full length protein. Truncating variants in APC are known to be pathogenic. This particular truncation has been reported in the literature in an individual affected with familial adenomatous polyposis (FAP) (PMID: 23159591). In addition, numerous pathogenic truncating variants have been reported downstream of this c.5490_5493delTGAA variant (PMID: 8940264, 11247896, 20434453). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000159590	SCV000579933	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-02	criteria provided, single submitter	clinical testing	The c.5490_5493delTGAA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 5490 to 5493, causing a translational frameshift with a predicted alternate stop codon (p.N1830Kfs*32). This alteration occurs at the 3' terminus of theAPC gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This mutation has been identified in 1/1591 patients undergoing clinical testing for familial adenomatous polyposis (FAP) (Kerr SE et al. J Mol Diagn 2013 Jan;15:31-43). It was also reported in an individual with colon polyps who was one of 10,030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000159590	SCV001347428	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual affected with familial adenomatous polyposis (PMID: 23159591) and one individual with colon polyps (PMID: 26681312). 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. Based on the available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262202	SCV001439989	pathogenic	Colorectal cancer	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV003534418	SCV002243694	pathogenic	Familial adenomatous polyposis 1	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1830Lysfs*32) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1014 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 individuals with familial adenomatous polyposis (FAP) (PMID: 8940264, 11247896, 20434453, 23159591). ClinVar contains an entry for this variant (Variation ID: 181835). 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.
Myriad Genetics, Inc.	RCV000234000	SCV004044702	pathogenic	Familial adenomatous polyposis 1	2023-05-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.