chr5-112839576-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.3982C>T(p.Gln1328Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
APC
NM_000038.6 stop_gained
NM_000038.6 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.14
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
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 88 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-112839576-C-T is Pathogenic according to our data. Variant chr5-112839576-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 92346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839576-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | c.3982C>T | p.Gln1328Ter | stop_gained | 16/16 | ENST00000257430.9 | NP_000029.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.3982C>T | p.Gln1328Ter | stop_gained | 16/16 | 5 | NM_000038.6 | ENSP00000257430 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2023 | This sequence change creates a premature translational stop signal (p.Gln1328*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1516 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 the literature (PMID: 8395941, 9101302, 14961559, 20685668, 26900293). ClinVar contains an entry for this variant (Variation ID: 92346). 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 | Myriad Genetics, Inc. | May 10, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 26, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 30, 2020 | PVS1_Strong, PS2, PM2, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2016 | This pathogenic variant is denoted APC c.3982C>T at the cDNA level and p.Gln1328Ter (Q1328X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through protein truncation. This variant has been reported in multiple individuals with a history of adenomatous polyposis (Paul 1993, Gismondi 1997, De Rosa 2003) and is considered pathogenic. - |
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Gln1328X variant was identified in 6 of 192 proband chromosomes (frequency: 0.031) from Italian individuals or families with familial adenomatous polyposis (Paul 1993, De Rosa 2003, Gismondi 1997). The variant is listed in the dbSNP database (ID#: rs398123121) “With Pathogenic allele” however no frequency information was provided. The variant was not found in 1000 Genomes Project, NHLBI Exome Sequencing Project (Exome Variant Server), or the Exome Aggregation Consortium (ExAC) databases. The variant was identified 2x by Emory Genetics in the ClinVar database classified as a pathogenic variant. In Clinvitae the variant is classified 1x as pathogenic; and was identified 20x in COSMIC (15x as somatic mutations: 11x from tumour and 9x from an unknown source). In the “InSiGHT Colon Cancer Database”, the variant was identified 4x with no classification. In the UMD-APC database the variant was identified 6x as “causal”. The p.Gln1328X variant leads to a premature stop codon at position 1328, which is predicted to lead to 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2019 | The p.Q1328* pathogenic mutation (also known as c.3982C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3982. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This mutation (also designated Q1328X) has been reported in multiple individuals with a clinical diagnosis of familial adenomatous polyposis (FAP) (de Oliveira JC et al. Cancer Med, 2019 May;8:2114-2122; De Rosa M et al. Hum. Mutat. 2003 Jun;21:655-6; Gismondi V et al. Hum. Mutat. 1997;9:370-3; Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2; Paul P et al. Hum. Mol. Genet. 1993 Jul;2:925-31). 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. - |
APC-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 16, 2022 | The APC c.3982C>T variant is predicted to result in premature protein termination (p.Gln1328*). This variant has been reported in many individuals with familial adenomatous polyposis coli (Table 1, Pedigree 1193, Paul et al. 1993. PubMed ID: 8395941; Table 1, De Rosa et al. 2003. PubMed ID: 14961559; Table 1, Gismondi et al. 1997. PubMed ID: 9101302; Supplement, Lagarde et al. 2010. PubMed ID: 20685668; Table 1, de Oliveira et al. 2019. PubMed ID: 30897307). It has also been reported in individuals with colorectal cancer (Table 3, Chang et al. 2016. PubMed ID: 26900293). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/92346/). Nonsense variants in APC are expected to be pathogenic. Although this variant occurs in the terminal exon of APC, pathogenic truncating variants have been reported downstream of this variant (The Human Gene Mutation Database, https://www.hgmd.cf.ac.uk; ClinVar, https://www.ncbi.nlm.nih.gov/clinvar/). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at