5-112838880-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.3286C>T(p.Gln1096*) 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: 4.64
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 173 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-112838880-C-T is Pathogenic according to our data. Variant chr5-112838880-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 156475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838880-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.3286C>T | p.Gln1096* | 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.3286C>T | p.Gln1096* | stop_gained | 16/16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+9908C>T | intron_variant | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2022 | For these reasons, this variant has been classified as Pathogenic. 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. 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. ClinVar contains an entry for this variant (Variation ID: 156475). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) syndrome (PMID: 10077047, 19331226, 20223039, 20685668). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1096*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1748 amino acid(s) of the APC protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 08, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 09, 2022 | This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the nuclear localization signal domains, beta-Catenin-, EB1-, and HDLG-binding sites (PMID: 17881494). This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 10077047, 19331226, 20223039, 20685668). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2022 | The p.Q1096* pathogenic mutation (also known as c.3286C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3286. This changes the amino acid from a glutamine 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 1748 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 alteration is reported in multiple individuals with a clinical diagnosis of FAP or AFAP from a variety of ethnic backgrounds (Gebert JF et al. Ann. Surg.,1999 Mar; 229:350-61; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Borosenko V et al. Anticancer Res., 2009 Feb;29:711-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
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
0.97, 0.97
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