5-112835090-CT-CTT

Position:

• chr5-112835090-CT-CTT

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.1886dup​(p.Leu629PhefsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). 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:4
• Conservation: PhyloP100: -1.12

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112835090-C-CT is Pathogenic according to our data. Variant chr5-112835090-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 216839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.1886dup	p.Leu629PhefsTer5	frameshift_variant	15/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1886dup	p.Leu629PhefsTer5	frameshift_variant	15/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Mar 07, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 216839). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 1324223, 20223039, 20685668, 24599579). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu629Phefs*5) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 29, 2015	This sequence change inserts 1 nucleotide in exon 15 of the APC mRNA (c.1886dupT), causing a frameshift at codon 629. This creates a premature translational stop signal (p.Leu629Phefs*5) and is expected to result in an absent or disrupted protein product. Truncating variants in APC are known to be pathogenic. This particular truncation was reported in individuals affected with familial adenomatous polyposis (PMID: 20223039, 20685668), and has been observed in affected patients in the Universal Mutation Database (PMID: 24599579). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2019

The c.1886dupT pathogenic mutation, located in coding exon 14 of the APC gene, results from a duplication of T at nucleotide position 1886, causing a translational frameshift with a predicted alternate stop codon (p.L629Ffs*5). This alteration was identified in 1/1164 unrelated German index patients with a clinical diagnosis of familial adenomatous polyposis (FAP) or attenuated familial adenomatous polyposis (AFAP) (Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114). This alteration was also identified in 2/934 French patients with FAP (Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2). 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: rs863224817; hg19: chr5-112170787;