rs1114167604

Variant names:

• chr5-112843640-GA-G
• rs1114167604
• NM_000038.6:c.8047delA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000038.6(APC):​c.8047delA​(p.Ile2683LeufsTer40) variant causes a frameshift change involving the alteration of a 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.62

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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. Fraction of 0.0568 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112843640-GA-G is Pathogenic according to our data. Variant chr5-112843640-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 428168.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.8047delA	p.Ile2683LeufsTer40	frameshift_variant	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.8047delA	p.Ile2683LeufsTer40	frameshift_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.229-13008delA		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 02, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8047delA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 8047, causing a translational frameshift with a predicted alternate stop codon. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of APC, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 122 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural analysis suggests this deletion removes a known motif (Thr2841-Ser2842-Val2843) needed for protein binding involved in regulation of protein function (Zhang Z et al. PLoS ONE, 2011 Aug;6:e23507; Slep KC. PLoS ONE, 2012 Nov;7:e50097). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1114167604; hg19: chr5-112179337;