rs587781910

Variant names:

• chr5-112838273-A-AGTGTCAG
• rs587781910
• NM_000038.6:c.2680_2686dupGTGTCAG

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.2680_2686dupGTGTCAG​(p.Ala896GlyfsTer18) 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, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.37

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 243 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112838273-A-AGTGTCAG is Pathogenic according to our data. Variant chr5-112838273-A-AGTGTCAG is described in ClinVar as [Pathogenic]. Clinvar id is 141652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.2680_2686dupGTGTCAG	p.Ala896GlyfsTer18	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.2680_2686dupGTGTCAG	p.Ala896GlyfsTer18	frameshift_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+9302_228+9308dupGTGTCAG		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

May 05, 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. -

Nov 24, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 141652). This sequence change creates a premature translational stop signal (p.Ala896Glyfs*18) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1948 amino acid(s) of the APC protein. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. 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. -

not provided Pathogenic:1

Nov 17, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This duplication of 7 nucleotides in APC is denoted c.2680_2686dupGTGTCAG at the cDNA level and p.Ala896GlyfsX18(A896GfsX18) at the protein level. The normal sequence, with the bases that are duplicated in braces, is AGAA[GTGTCAG]CCAT. The duplication causes a frameshift, which changes an Alanine to a Glycine at codon 896, and creates a premature stop codon at position 18 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. The loss of these residues disrupts several functional domains and regions responsible for down-regulation (Azzopardi 2008, UniProt). APC c.2680_2686dupGTGTCAG. also denoted as APC c.2680_2686dup7, has been observed in association with Familial Adenomatous Polyposis (Kerr 2013). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 02, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2680_2686dupGTGTCAG pathogenic mutation, located in coding exon 15 of the APC gene, results from a duplication of GTGTCAG at nucleotide positions 2680 to 2686, causing a translational frameshift with a predicted alternate stop codon. This mutation has been previously reported in the literature, though clinical history was not provided (Kerr, SE et al. J Mol Diagn. 2013 Jan;15(1):31-43). 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

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781910; hg19: chr5-112173970;