5-112839978-AAGAG-A

Position:

• chr5-112839978-AAGAG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.4391_4394del​(p.Glu1464ValfsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K1462K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.78

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 324 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112839978-AAGAG-A is Pathogenic according to our data. Variant chr5-112839978-AAGAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839978-AAGAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4391_4394del	p.Glu1464ValfsTer8	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4391_4394del	p.Glu1464ValfsTer8	frameshift_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 10, 2020	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, this variant has been reported in individuals affected with familial adenomatous polyposis (FAP; PMID: 15108286, 16088911, 20223039, 21643010), an FAP somatic mosaicism case (PMID: 17486639), and a Gardner fibroma case in the literature (PMID: 29026543). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2023	The c.4391_4394delAGAG pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 4391 to 4394, causing a translational frameshift with a predicted alternate stop codon (p.E1464Vfs*8). This mutation has been reported in multiple patients with a clinical diagnosis of familial adenomatous polyposis (FAP) or attenuated FAP (AFAP) (Armstrong JG et al. Hum. Mutat., 1997;10:376-80; Gismondi V et al. Hum. Mutat., 1997;9:370-3; Bisgaard ML et al. Hum. Mutat., 2004 May;23:522; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Kim DW et al. Hum. Mutat., 2005 Sep;26:281; Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2; Rohlin A et al. Oncogene, 2011 Dec;30:4977-89; Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change deletes four bases from exon 11 of the APC mRNA (c.4391_4394delAGAG), causing a frameshift after codon 1464 and the creation of a premature translation stop signal 8 amino acid residues later, p.(Glu1464Valfs). This is expected to result in an absent or disrupted protein product. This sequence change has been reported in the literature in individuals affected with familial adenomatous polyposis (FAP) (PMID: 20685668, 15108286, 16088911, 21643010, 20223039, 23159591). Truncating variants in APC are known to be pathogenic. The mutation database Clinvar contains entries for this variant (Variation ID:812). -

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 20, 2023	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: 812). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 15108286, 16088911, 20223039, 20685668, 21643010, 23159591). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1464Valfs*8) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1380 amino acid(s) of the APC protein. 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. -

Periampullary adenoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1993

- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Glu1464ValfsX8 deletion has been previously reported in the literature in 1 of 54 chromosomes from individuals with familial adenomatous polyposis (Gismondi 1997). is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1464 and leads to a premature stop codon 8 amino acids downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of FAP. Notably, this deletion occurs in the last exon of the APC gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate the hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. However, this is the type of alteration that is expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 2024

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); Also known as 4393del4; This variant is associated with the following publications: (PMID: 9101302, 16088911, 21643010, 17486639, 20685668, 20223039, 29026543, 23159591, 15108286, 31159747, 34873480) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906234; hg19: chr5-112175675;