GeneBe

rs121913224

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001407446.1(APC):​c.4011_4015delAAAGA​(p.Glu1337AspfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000821 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E1337E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

APC
NM_001407446.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:45U:1O:3

Conservation

PhyloP100: 6.22

Publications

114 publications found
Variant links:
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 polyposis
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • desmoid tumor
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
  • familial adenomatous polyposis 1
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • gastric adenocarcinoma and proximal polyposis of the stomach
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
  • sarcoma
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • APC-related attenuated familial adenomatous polyposis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Turcot syndrome with polyposis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Cenani-Lenz syndactyly syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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 825 pathogenic variants in the truncated region.
PP5
Variant 5-112839514-TAAAAG-T is Pathogenic according to our data. Variant chr5-112839514-TAAAAG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 816.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407446.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
APC
NM_000038.6
MANE Select
c.3927_3931delAAAGAp.Glu1309AspfsTer4
frameshift
Exon 16 of 16NP_000029.2
APC
NM_001407446.1
c.4011_4015delAAAGAp.Glu1337AspfsTer4
frameshift
Exon 16 of 16NP_001394375.1
APC
NM_001354896.2
c.3981_3985delAAAGAp.Glu1327AspfsTer4
frameshift
Exon 17 of 17NP_001341825.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
APC
ENST00000257430.9
TSL:5 MANE Select
c.3927_3931delAAAGAp.Glu1309AspfsTer4
frameshift
Exon 16 of 16ENSP00000257430.4
APC
ENST00000508376.6
TSL:1
c.3927_3931delAAAGAp.Glu1309AspfsTer4
frameshift
Exon 17 of 17ENSP00000427089.2
APC
ENST00000502371.3
TSL:1
n.*2125_*2129delAAAGA
non_coding_transcript_exon
Exon 12 of 12ENSP00000484935.2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000797
AC:
2
AN:
251040
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461874
Hom.:
0
AF XY:
0.00000550
AC XY:
4
AN XY:
727238
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000809
AC:
9
AN:
1112000
Other (OTH)
AF:
0.0000166
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
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000113
Hom.:
0

ClinVar

ClinVar submissions as Germline
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar

Computational scores

Publications

Other links and lift over

dbSNP: rs121913224; hg19: chr5-112175211; COSMIC: COSV57321812; COSMIC: COSV57321812; API