chr5-112839514-TAAAAG-T
Variant summary
Our verdict is . The variant received 22 classification points (ACMG Germline Pathogenicity v2019): 22P and 0B. PVS1PS3PM2PP5_Very_Strong
Pathogenic
The NM_000038.6(APC):c.3927_3931delAAAGA (p.Glu1309AspfsTer4) variant causes a frameshift change. This is a loss-of-function variant that does not trigger NMD. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant allele was found at a cumulative frequency of 0.00000821 (AC=12) in the gnomAD database across 1,461,874 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000381. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000058712: "In vitro functional studies provide some evidence that the p.Glu1309fs variant may impact protein function (Dihlmann 2009)."".
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
APC
NM_000038.6 frameshift
NM_000038.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.22
Publications
116 publications found
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]
APC Gene-Disease associations (from GenCC):
- classic or attenuated familial adenomatous polyposisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- desmoid tumorInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
- familial adenomatous polyposis 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- gastric adenocarcinoma and proximal polyposis of the stomachInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- Cenani-Lenz syndactyly syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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new If you want to explore the variant's impact on the transcript NM_000038.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACMG Germline Pathogenicity v2019
Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.
Classification was made for transcript
Our verdict: Pathogenic. The variant received 22 points.
PVS1
Non-NMD frameshift: ≥4 downstream pathogenic — very strong evidence preserved (PVS1); Frameshift (exon 16 of 16) at amino acid 1309 of 2843; NMD not predicted. 863 pathogenic variants downstream support preserved loss-of-function impact. No in-frame stop codon was found in the shifted reading frame.
PS3
Well-established functional study supports damaging effect (PS3); SCV000058712: "In vitro functional studies provide some evidence that the p.Glu1309fs variant may impact protein function (Dihlmann 2009)."
PM2
Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000381 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00124) — PM2 moderate.
PP5
ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s).
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | MANE Select | c.3927_3931delAAAGA | p.Glu1309AspfsTer4 | frameshift | Exon 16 of 16 | NP_000029.2 | |||
| APC | c.4011_4015delAAAGA | p.Glu1337AspfsTer4 | frameshift | Exon 16 of 16 | NP_001394375.1 | ||||
| APC | c.3981_3985delAAAGA | p.Glu1327AspfsTer4 | frameshift | Exon 17 of 17 | NP_001341825.1 | R4GMU6 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | TSL:5 MANE Select | c.3927_3931delAAAGA | p.Glu1309AspfsTer4 | frameshift | Exon 16 of 16 | ENSP00000257430.4 | P25054-1 | ||
| APC | TSL:1 | c.3927_3931delAAAGA | p.Glu1309AspfsTer4 | frameshift | Exon 17 of 17 | ENSP00000427089.2 | P25054-1 | ||
| APC | TSL:1 | n.*2125_*2129delAAAGA | 3_prime_UTR | Exon 12 of 12 | ENSP00000484935.2 | A0A087X2F3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000797 AC: 2AN: 251040 AF XY: 0.00000737 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
251040
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461874Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727238 show subpopulations
GnomAD4 exome
AF:
AC:
12
AN:
1461874
Hom.:
AF XY:
AC XY:
4
AN XY:
727238
show subpopulations
African (AFR)
AF:
AC:
1
AN:
33478
American (AMR)
AF:
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
1
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
9
AN:
1112000
Other (OTH)
AF:
AC:
1
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
2
3
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5
0.00
0.20
0.40
0.60
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
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8
10
<30
30-35
35-40
40-45
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
Local populations
ToMMo 61KJPN (+60KJPN MNV)
AF:
AC:
2
AN:
122716
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:reviewed by expert panel
Pathogenic
VUS
Benign
Condition
18
1
-
Familial adenomatous polyposis 1 (20)
14
-
-
not provided (14)
3
-
-
Hereditary cancer-predisposing syndrome (3)
2
-
-
Familial multiple polyposis syndrome (2)
1
-
-
ADENOMATOUS POLYPOSIS COLI WITH CONGENITAL CHOLESTEATOMA (1)
1
-
-
APC-related disorder (1)
1
-
-
Carcinoma of colon (1)
1
-
-
Classic or attenuated familial adenomatous polyposis (1)
1
-
-
Colon adenocarcinoma (1)
1
-
-
Colorectal cancer (2)
1
-
-
Gardner syndrome (1)
1
-
-
Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach (1)
1
-
-
Intestinal polyp;C0236048:Gastric polyposis;C0578477:Duodenal polyposis;C1868071:Adenomatous colonic polyposis;C4023010:Hyperplastic colonic polyposis (1)
-
-
-
Neoplasm (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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