rs387906236

Positions:

• chr5-112840204-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000038.6(APC):​c.4612_4613del​(p.Glu1538IlefsTer5) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.26

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 16 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 31 pathogenic variants in the truncated region.
• PP5: Variant 5-112840204-CAG-C is Pathogenic according to our data. Variant chr5-112840204-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112840204-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.4612_4613del	p.Glu1538IlefsTer5	frameshift_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.4612_4613del	p.Glu1538IlefsTer5	frameshift_variant	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152074 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

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

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74274

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change creates a premature translational stop signal (p.Glu1538Ilefs*5) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1306 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: 8162051, 8594558, 20223039, 20513532, 20685668, 21643010, 21779980, 22987206). ClinVar contains an entry for this variant (Variation ID: 823). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 11, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 05, 2023	- -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 28, 2020

The p.Glu1538IlefsX5 variant in APC has been previously reported in at least 6 individuals with APC-associated polyposis conditions: 3 with familial adenomatous polyposis (FAP), 3 individuals with Gardner syndrome, and 4 individuals with suspected FAP (Gayther 1994 PMID: 8162051, Armstrong 1997 PMID: 9375853, Friedl 2005 PMID: 20223039, Jang 2010 PMID: 20513532, Lagarde 2010 PMID: 20685668, Jarry 2011 PMID: 21779980, Rohlin 2011 PMID: 21643010, Schwarzová 2013 PMID: 22987206). This variant was also reported by other clinical laboratories in ClinVar (Variation ID: 823) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1538 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~46% of the coding region, with 1302 amino acids removed. Truncating variants in the last exon of APC, including multiple variants downstream of this variant, have been reported in individuals with FAP. Furthermore, this truncation is predicted to remove the EB1 and APC-basic domains of the APC protein, and in vitro studies have shown that these domains are important regions for APC-mediated microtubule stability and F-actin interactions (Moseley 2007 PMID 17293347, Wen 2004 PMID 15311282). In summary, this variant meets criteria to be classified as pathogenic for APC-associated polyposis conditions, including autosomal dominant FAP and Gardner syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Strong. -

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

APC NM_000038.5 exon 15 p.Glu1538Ilefsx5 (c.4612_4613del): This variant has been reported in the literature in at least 8 individuals with Familial Adenomatous Polyposis (FAP) (Gayther 1994 PMID:8162051, Friedl 2005 PMID:20223039, Jang 2010 PMID:20513532, Lagarde 2010 PMID:20685668, Jarry 2011 PMID:21779980, Rohlin 2011 PMID:21643010, Schwarzova 2013 PMID:22987206). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:823). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of two nucleotides and creates a premature stop codon 5 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Zhang 2017 PMID:28423402). Of note, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. However this variant is predicted to affect approximately 45% of the protein and other variants downstream have been reported as Pathogenic. Furthermore, evidence in the literature suggests that variants cluster in this region (Gayther 1994 PMID:8162051). In summary, this variant is classified as pathogenic based on the data above. -

Gardner syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1997

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2015

The c.4612_4613delGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides between nucleotide positions 4612 and 4613, causing a translational frameshift with a predicted alternate stop codon. This mutation has been detected in multiple individuals with clinical diagnoses of AFAP or FAP (Friedl W, et al. Hered Cancer Clin Pract 2005;3(3):95-114, Vandrovcová J, et a. Hum. Mutat. 2004;23(4):397, Jang YH, et al. Cancer Genet. Cytogenet. 2010;200(1):34-9, Gayther SA, et al. Hum. Mol. Genet. 1994;3(1):53-6, Armstrong JG, et al. Hum. Mutat. 1997;10(5):376-80). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

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: rs387906236; hg19: chr5-112175901;