rs863224457

Variant names:

• chr5-112839514-TAAAA-T
• rs863224457
• NM_000038.6:c.3921_3924delAAAA

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.3921_3924delAAAA​(p.Ile1307MetfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.22

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 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 99 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112839514-TAAAA-T is Pathogenic according to our data. Variant chr5-112839514-TAAAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839514-TAAAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.3921_3924delAAAA	p.Ile1307MetfsTer13	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.3921_3924delAAAA	p.Ile1307MetfsTer13	frameshift_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+10543_228+10546delAAAA		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

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/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

May 20, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 4 nucleotides in exon 16 of the APC mRNA (c.3921_3924delAAAA), causing a frameshift at codon 1307. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Ile1307Metfs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated APC protein. Truncating variants in APC are known to be pathogenic. This particular truncation has been previously reported in three families affected with Familial Adenomatous Polyposis (PMID: 14729851, 19029688, 26163615). For these reasons, this variant has been classified as Pathogenic. -

May 09, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Pathogenic:1

Sep 12, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant creates a premature stop codon in the last exon of the APC gene. While this is not expected to trigger nonsense-mediated decay of the affected allele, the resulting disruption of approximately 54% of the coding sequences of the APC gene is predicted to significantly impact protein function. In the published literature, this variant has been reported in individuals and families with FAP (PMIDs: 26163615 (2015), 19029688 (2008), 14729851 (2004)). A similar truncating variant, c.3920_3923del (p.Ile1307Lysfs*13, also known as 3938del4) has also been described as deleterious in a family with FAP (PMID: 9341879 (1997)). The c.3921_3924del (p.Ile1307Metfs*13) variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 01, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3921_3924delAAAA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides between nucleotide positions 3921 and 3924, causing a translational frameshift with a predicted alternate stop codon. This pathogenic mutation has been reported in two children from one Polish family who were diagnosed with FAP at ages 8 years and 4 years (Plawski A et al. J Med Genet. 2004 Jan;41(1):e11). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

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: rs863224457; hg19: chr5-112175211; COSMIC: COSV57400237; COSMIC: COSV57400237;