chr5-112838271-G-T

Position:

• chr5-112838271-G-T

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.2677G>T​(p.Glu893Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.60

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 245 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112838271-G-T is Pathogenic according to our data. Variant chr5-112838271-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838271-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.2677G>T	p.Glu893Ter	stop_gained	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.2677G>T	p.Glu893Ter	stop_gained	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2016	This variant is denoted APC c.2677G>T at the cDNA level and p.Glu893Ter (E893X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA). This variant is predicted to cause loss of normal protein function through protein truncation. This variant has been reported in individuals with Familial Adenomatous Polyposis and is considered pathogenic (Hutter 2001, Kohda 2016). -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 07, 2023	This nonsense variant causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals and families with familial adenomatous polyposis (FAP) (PMIDs: 20685668 (2010), 19444466 (2009), 11748858 (2001)). Based on the available information, this variant is classified as pathogenic. -

Familial adenomatous polyposis 1 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Oct 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 05, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2021	This variant is not present in population databases (ExAC no frequency). 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. 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419997). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 11748858, 19444466, 20685668). This sequence change creates a premature translational stop signal (p.Glu893*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1951 amino acid(s) of the APC protein. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Glu893X variant was identified in 4 of 122 proband chromosomes (frequency: 0.03) from individuals or families with colorectal cancer (Hutter 2001, Zauber 2014). The variant was also identified in HGMD, “InSiGHT Colon Cancer Database”, and UMD (5X as an unclassified variant). Of note, this variant occurs in the last exon of the gene and truncating variants in this region are sometimes not subject to nonsense mediated RNA decay, although further study would be needed to verify this. The p.Glu893X variant leads to a premature stop codon at position 893, which is predicted to lead to 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 and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 14, 2020

This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.99, 0.99
GERP RS		5.9

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: rs199740875; hg19: chr5-112173968; COSMIC: COSV57332855; COSMIC: COSV57332855;