rs1554086196

Positions:

• chr5-112840371-AAGCC-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.4782_4785del​(p.Ala1595ArgfsTer54) 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. K1593K) 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:6
• Conservation: PhyloP100: 7.15

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 233 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112840371-AAGCC-A is Pathogenic according to our data. Variant chr5-112840371-AAGCC-A is described in ClinVar as [Pathogenic]. Clinvar id is 433668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4782_4785del	p.Ala1595ArgfsTer54	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4782_4785del	p.Ala1595ArgfsTer54	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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2023	This variant deletes 4 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal in the last exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the B-catenin binding region, nuclear localization motifs, EB1-binding and DLG-binding domains (PMID: 23185543). This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 16478792, 20434453, 27158207). In addition, truncating variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 628123, 653103, 486770). 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	Jul 09, 2021	The c.4782_4785delAGCC pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 4782 to 4785, causing a translational frameshift with a predicted alternate stop codon (p.A1595Rfs*54). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1249 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This alteration has been identified in several individuals with familial adenomatous polyposis (FAP) (Mutoh M et al. Jpn. J. Clin. Oncol., 2006 Mar;36:166-71; Castellsagué E et al. Gastroenterology, 2010 Aug;139:439-47, 447.e1; Jung SM et al. World J Gastroenterol, 2016 May;22:4380-8). 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. -

Familial adenomatous polyposis 1 Pathogenic:1

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. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Ala1595ArgfsX54 variant was identified in HGMD, and in the literature in an individual with attenuated familial adenomatous polyposis (Castellsague 2010). The p.Ala1595ArgfsX54 variant deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1595 and leads to a premature stop codon 54 codons 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 disease in familial adenomatous polyposis. It should be noted that the p.Ala1595ArgfsX54 variant 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 this hypothesis, and it is currently not possible to determine whether or not this might influence the severity of the disorder. In concordance with this, Castellsague (2010) found that the transcriptional expression of the variant in an affected individual was within normal range, suggesting an absence of nonsense mediated RNA decay, though the authors note that there was no clear phenotypic correlation observed between clinical features and exon location of APC mutations in their cohort. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Classic or attenuated familial adenomatous polyposis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 15, 2023

This variant deletes 4 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal in the last exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the B-catenin binding region, nuclear localization motifs, EB1-binding and DLG-binding domains (PMID: 23185543). This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 16478792, 20434453, 27158207). In addition, truncating variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 628123, 653103, 486770). 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. -

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: rs1554086196; hg19: chr5-112176068;