rs1554088762

chr5-112843523-AATTT-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000038.6(APC):c.7932_7935del(p.Tyr2645LysfsTer14) 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. I2644I) 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: 4.55

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 14 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 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112843523-AATTT-A is Pathogenic according to our data. Variant chr5-112843523-AATTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 486770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112843523-AATTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.7932_7935del	p.Tyr2645LysfsTer14	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.7932_7935del	p.Tyr2645LysfsTer14	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

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 16, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 05, 2020	This variant has been observed in individuals affected with familial adenomatous polyposis (FAP) and attenuated FAP with or without extra-colonic phenotypes (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This variant is also known as Ile2644fs*7 in the literature. ClinVar contains an entry for this variant (Variation ID: 486770). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Tyr2645Lysfs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 199 amino acids of the APC protein. For these reasons, this variant has been classified as Pathogenic. 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2017

The c.7932_7935delTTAT pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 7932 to 7935, causing a translational frameshift with a predicted alternate stop codon (p.Y2645Kfs*14). Premature stop codons are typically deleterious in nature; however, this stop codon, which occurs at the 3' terminus of APC, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 199 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). This alteration has been described in numerous individuals with classic and attenuated Familial Adenomatous Polyposis and appears to be associated with the development of extra-colonic manifestations, particularly desmoid tumors (Burger B et al. Oncologist, 2011 Dec;16:1698-705; Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A., 1992 May;89:4452-6; Ikenoue T et al. Hum Genome Var, 2015 Mar;2:15011; Brensinger JD et al. Gut, 1998 Oct;43:548-52; Groden J et al. Am. J. Hum. Genet., 1993 Feb;52:263-72). This alteration is expected to result in loss of function by premature protein truncation. 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: rs1554088762; hg19: chr5-112179220;