5-112838007-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.2413C>T(p.Arg805*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.67
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]
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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 263 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-112838007-C-T is Pathogenic according to our data. Variant chr5-112838007-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 127281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838007-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.2413C>T | p.Arg805* | 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.2413C>T | p.Arg805* | stop_gained | 16/16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
| ENSG00000258864 | ENST00000520401.1 | n.228+9035C>T | intron_variant | 3 | ENSP00000454861.1 |
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:12Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Familial multiple polyposis syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 15, 2021 | Variant summary: APC c.2413C>T (p.Arg805X) results in a premature termination codon located in the last exon, which is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a large truncation of the encoded protein, removing the basic domain (amino acids 2224-2575; IPR009234) and the EB-1 binding domain (amino acid 2670-2843; IPR009232). Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250860 control chromosomes (gnomAD). c.2413C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (e.g. Dobbie_1996, Iaquinto_2008, deOliveira_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | Sep 01, 2015 | - - |
Familial adenomatous polyposis 1 Pathogenic:2
| 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.Arg805*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2039 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: 8730280, 19531215, 20223039, 20649969, 20924072, 30897307). ClinVar contains an entry for this variant (Variation ID: 127281). 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 04, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Desmoid disease, hereditary Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 15, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 8730280, 30897307; ClinVar 127281] - |
Classic or attenuated familial adenomatous polyposis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 09, 2023 | The c.2413C>T (p.Arg805*) variant in the APC gene is located on the exon 16 and is predicted to introduce a premature translation termination codon (p.Arg805*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with familial adenomatous polyposis (PMID: 30897307, 31113927, 26446593, 19029688, 20649969). Loss-of-function variants of APC are known to be pathogenic and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with familial adenomatous polyposis/colorectal cancer (PMID: 26446593, 23159591, 31591141, 33769591). The variant is reported in ClinVar as pathogenic (ID: 127281). The variant is absent in the general population database (gnomAD). Therefore, the c.2413C>T (p.Arg805*) variant of APC has been classified as pathogenic. - |
APC-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2024 | The APC c.2413C>T variant is predicted to result in premature protein termination (p.Arg805*). This variant has been reported in individuals with adenomatous polyposis coli (Table 1, Dobbie et al. 1996. PubMed ID: 8730280; Tables 1 and 4, de Oliveira et al. 2019. PubMed ID: 30897307; Table 1, Lee et al. 2022. PubMed ID: 35189564). This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/127281/). Nonsense variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 21, 2022 | The p.R805* pathogenic mutation (also known as c.2413C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2413. This changes the amino acid from an arginine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 257 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This variant was previously described in an individual with polyposis and a family history of colorectal cancer (Dobbie Z et al. J. Med. Genet. 1996 Apr; 33(4):274-80). It was also seen in two individuals diagnosed with familial adenomatous polyposis (FAP) (Gutierrez Sanchez LH et al. Gastrointest. Endosc. 2018 Mar;87(3):648-656.e3). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Neoplasm Other:1
| -, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach;C5679615:APC-related attenuated familial adenomatous polyposis Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Pathogenic and reported on 02-04-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
0.94, 0.93
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