rs878853420

chr5-112835079-CCAGA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000038.6(APC):c.1875_1878del(p.Asn627LeufsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q625Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.51

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-112835079-CCAGA-C is Pathogenic according to our data. Variant chr5-112835079-CCAGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 236565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112835079-CCAGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1875_1878del	p.Asn627LeufsTer2	frameshift_variant	15/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1875_1878del	p.Asn627LeufsTer2	frameshift_variant	15/16	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:5

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 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	Invitae	Apr 07, 2023	This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 8381580, 19029688, 20685668, 20924072). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn627Leufs*2) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). ClinVar contains an entry for this variant (Variation ID: 236565). For these reasons, this variant has been classified as Pathogenic. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Asn627LeufsX2 variant was identified in 3 of 1192 proband chromosomes (frequency: 0.003) from French, Spanish and Polish individuals or families with FAP (Olschwang 1993, Plawski 2008, Rivera 2011). The variant was identified in the following databases: Clinvitae (as pathogenic), COSMIC (1x in an adenocarcinoma), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar (pathogenic by Invitae), and UMD (1x with a “causal” classification); but the variant was not identified in dbSNP, the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium, the genome Aggregation Database (beta), COGR, MutDB, or the Zhejiang Colon Cancer Database (LOVD). The c.1875_1878del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 627 and leads to a premature stop codon 2 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. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

-

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.1875_1878delGACA pathogenic mutation, located in coding exon 14 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 1875 to 1878, causing a translational frameshift with a predicted alternate stop codon (p.N627Lfs*2). This mutation (designated CAGACA->CA) was first reported in 1/160 French patients with adenomatous polyposis (Olschwang S et al. Am. J. Hum. Genet., 1993 Feb;52:273-9), and it has since been identified in 3/934 French patients with familial adenomatous polyposis (FAP) (Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2), 1/300 unrelated Polish FAP families (Plawski A et al. J. Appl. Genet., 2008;49:407-14), and 1/136 Spanish families with classical FAP (Rivera B et al. Ann. Oncol., 2011 Apr;22:903-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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: rs878853420; hg19: chr5-112170776;