rs863225322

chr5-112837562-AAGAG-Achr5-112837562-AAGAG-AAG

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.1972_1975del(p.Glu658ThrfsTer11) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R657R) 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:7
• 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 1035 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112837562-AAGAG-A is Pathogenic according to our data. Variant chr5-112837562-AAGAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 217940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112837562-AAGAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1972_1975del	p.Glu658ThrfsTer11	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1972_1975del	p.Glu658ThrfsTer11	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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2023	This sequence change creates a premature translational stop signal (p.Glu658Thrfs*11) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2186 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis and several colorectal polyps (PMID: 2068568, 20564245, 23159591, 25604157). ClinVar contains an entry for this variant (Variation ID: 217940). 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. 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 03, 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	Baylor Genetics	Nov 01, 2022	- -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20564245, 23159591, 17293347, 9824584, 15311282, 1316610, 27081525, 8381579, 22135120, 20685668) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2022	The c.1972_1975delGAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 1972 to 1975, causing a translational frameshift with a predicted alternate stop codon (p.E658Tfs*11). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 2,186 AA of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). This mutation has been reported in cohorts of individuals with familial adenomatous polyposis and in patients referred for APC testing (Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2; Garzón-Benavides M et al. Rev. Esp. Enferm. Dig. 2010 Nov;102:653-7; Miclea RL et al. J. Bone Miner. Res. 2010 Dec;25:2624-32; Kerr SE et al. J. Mol. Diagn. 2013 Jan;15:31-43; Out AA et al. Fam. Cancer 2015 Jun;14:247-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2021	This variant deletes 4 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with multiple polyps (PMID: 25604157) or familial adenomatous polyposis (PMID: 20564245, 20685668, 21142386, 23159591, 29122597). 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

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: rs863225322; hg19: chr5-112173259;