rs1554085029

chr5-112839060-GAAGA-G

Variant summary

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

The NM_000038.6(APC):c.3467_3470del(p.Glu1156GlyfsTer8) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E1156E) 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:3
• Conservation: PhyloP100: 6.91

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 616 pathogenic variants in the truncated region.
• PP5: Variant 5-112839060-GAAGA-G is Pathogenic according to our data. Variant chr5-112839060-GAAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 433646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839060-GAAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.3467_3470del	p.Glu1156GlyfsTer8	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.3467_3470del	p.Glu1156GlyfsTer8	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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The p.Glu1156GlyfsX8 variant variant was identified in 6 of 2654 proband chromosomes (frequency: 0.002) from German, Spanish, American and Japanese individuals or families with FAP or AFAP (Gomez-Fernandez 2009, Miyoshi 1992, Friedl 2005); however, control chromosomes were not evaluated in these studies. In a series of 30 gastric adenomas screened for APC mutations, one was found to carry the variant, supporting a role for this APC gene mutation in early stages of gastric adenoma development (Tamura 1994). The variant was identified in, HGMD, COSMIC, InSiGHT Colon Cancer Gene Variant Database, and UMD (2X as unvalidated). In UMD the variant was identified with a co-occurring APC unclassified variant (c.2567delG). The p.Glu1156GlyfsX8 variant leads to a premature stop codon at position 1163, 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.Notably, this variant occurs 50 base pairs before the penultimate exon junction in the last exon of the 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 summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Familial adenomatous polyposis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 08, 2023

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2017

The c.3467_3470delAAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 3467 to 3470, causing a translational frameshift with a predicted alternate stop codon (p.E1156Gfs*8). This mutation has been reported in multiple patients with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A., 1992 May;89:4452-6; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Gómez-Fernández N et al. BMC Med. Genet., 2009 Jun;10:57). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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: rs1554085029; hg19: chr5-112174757; COSMIC: COSV57324641; COSMIC: COSV57324641;