Submissions for variant NM_000038.6(APC):c.1972_1975del (p.Glu658fs)

dbSNP: rs863225322

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515483	SCV000282708	pathogenic	Familial adenomatous polyposis 1	2024-09-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu658Thrfs*11) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2186 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 and several colorectal polyps (PMID: 2068568, 20564245, 23159591, 25604157). ClinVar contains an entry for this variant (Variation ID: 217940). 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, internal data). 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.
GeneDx	RCV000202030	SCV000293371	pathogenic	not provided	2023-09-25	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: 20564245, 23159591, 17293347, 9824584, 15311282, 1316610, 27081525, 8381579, 22135120, 20685668)
Ambry Genetics	RCV001013903	SCV001174544	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-28	criteria provided, single submitter	clinical testing	The c.1972_1975delGAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 1972 to 1975, causing a translational frameshift with a predicted alternate stop codon (p.E658Tfs*11). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 2,186 AA 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 alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). This mutation has been reported in cohorts of individuals with familial adenomatous polyposis and in patients referred for APC testing (Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2; Garzón-Benavides M et al. Rev. Esp. Enferm. Dig. 2010 Nov;102:653-7; Miclea RL et al. J. Bone Miner. Res. 2010 Dec;25:2624-32; Kerr SE et al. J. Mol. Diagn. 2013 Jan;15:31-43; Out AA et al. Fam. Cancer 2015 Jun;14:247-57). 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.
Color Diagnostics, LLC DBA Color Health	RCV001013903	SCV001355993	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-15	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with multiple polyps (PMID: 25604157) or familial adenomatous polyposis (PMID: 20564245, 20685668, 21142386, 23159591, 29122597). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV002515483	SCV004043973	pathogenic	Familial adenomatous polyposis 1	2023-05-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV002515483	SCV004207383	pathogenic	Familial adenomatous polyposis 1	2022-11-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202030	SCV000256938	pathogenic	not provided		no assertion criteria provided	research