rs878853422

chr5-112837621-TAGTC-T

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.2031_2034del(p.Ser678MetfsTer39) 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:6
• 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 1017 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112837621-TAGTC-T is Pathogenic according to our data. Variant chr5-112837621-TAGTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 236568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112837621-TAGTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.2031_2034del	p.Ser678MetfsTer39	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.2031_2034del	p.Ser678MetfsTer39	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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 05, 2023	This sequence change creates a premature translational stop signal (p.Ser678Metfs*39) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2166 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 (PMID: 17411426). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236568). 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	Invitae	Jan 01, 2016	This sequence change deletes 4 nucleotides from exon 16 of the APC mRNA (c.2031_2034delCAGT), causing a frameshift at codon 678. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Ser678Metfs*39). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated APC protein with more than 2100 amino acid residues (75%) deleted. Truncating variants in APC are known to be pathogenic. This particular truncation has been reported in the literature in individuals with familial adenomatous polyposis (PMID: 17411426). 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. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ser678MetfsX39 variant was identified in the literature in two families with familial adenomatous polyposis (both classic and attenuated phenotypes) (Strekova 2007). The variant was also identified in the HGMD, InSiGHT Colon Cancer Gene Variant Database, and the “Zhejiang Colon Cancer Database”. The p.Ser678MetfsX39 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 678 and leads to a premature stop codon 39 codons downstream. This alteration is then predicted to result in 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 in the last exon of the gene and stop codon (or nonsense) mutations in this region are not always subject 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jun 27, 2018

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The c.2031_2034delCAGT pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 2031 to 2034, causing a translational frameshift with a predicted alternate stop codon (p.S678Mfs*39). This alteration has been reported in two Czech families with FAP or AFAP phenotype (Stekrova J et al. BMC Med. Genet., 2007 Apr;8:16). This alteration has also been reported in a Han Chinese family with FAP (Pang M et al. Mol Med Rep, 2018 Aug;18:1423-1432). In addition to the clinical data presented in the literature, 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: rs878853422; hg19: chr5-112173318;