rs878853454

Variant names:

• chr5-112840617-G-GT
• rs878853454
• NM_000038.6:c.5025dupT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000038.6(APC):​c.5025dupT​(p.Arg1676fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.118
• Publications: 0 publications found

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]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 434 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112840617-G-GT is Pathogenic according to our data. Variant chr5-112840617-G-GT is described in ClinVar as Pathogenic. ClinVar VariationId is 236613.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.5025dupT	p.Arg1676fs	frameshift_variant, stop_gained	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.5025dupT	p.Arg1676fs	frameshift_variant, stop_gained	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+11647dupT		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Mar 28, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change inserts 1 nucleotide in exon 16 of the APC mRNA (c.5025dupT), causing a frameshift at codon 1676. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Arg1676*). While this is not anticipated to result in nonsense mediated decay, it is expected to remove the final ~1150 amino acid residues of APC, which is equivalent to ~40% of the total protein. While this particular variant has not been reported in the literature, numerous pathogenic truncating variants have been reported downstream of this c.5025dupT variant in individuals affected with classical familial adenomatous polyposis (FAP), attenuated FAP, or desmoid tumor, suggesting that the C-terminal portion of the protein is clinically important (PMID: 23159591, 8940264, 9824584, 8968744). For these reasons, this variant has been classified as Pathogenic.

Mar 28, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, numerous pathogenic truncating variants have been reported downstream of this c.5025dupT variant in individuals affected with classical familial adenomatous polyposis (FAP), attenuated FAP, or desmoid tumor, suggesting that the C-terminal portion of the protein is clinically important (PMID: 23159591, 8940264, 9824584, 8968744). This sequence change inserts 1 nucleotide in exon 16 of the APC mRNA (c.5025dupT), causing a frameshift at codon 1676. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Arg1676*). While this is not anticipated to result in nonsense mediated decay, it is expected to remove the final ~1150 amino acid residues of APC, which is equivalent to ~40% of the total protein.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878853454; hg19: chr5-112176314;