rs769482880

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000038.6(APC):​c.669A>C​(p.Gln223His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,610,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q223E) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 32)
Exomes š‘“: 0.000029 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

5
12
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 1.94

Publications

6 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: Uncertain_significance. The variant received 1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APCNM_000038.6 linkc.669A>C p.Gln223His missense_variant Exon 7 of 16 ENST00000257430.9 NP_000029.2 P25054-1Q4LE70

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkc.669A>C p.Gln223His missense_variant Exon 7 of 16 5 NM_000038.6 ENSP00000257430.4 P25054-1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000159
AC:
4
AN:
251000
AF XY:
0.0000221
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:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000288
AC:
42
AN:
1458706
Hom.:
0
Cov.:
30
AF XY:
0.0000289
AC XY:
21
AN XY:
725602
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33432
American (AMR)
AF:
0.00
AC:
0
AN:
44662
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26062
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39434
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85762
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53154
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5740
European-Non Finnish (NFE)
AF:
0.0000360
AC:
40
AN:
1110246
Other (OTH)
AF:
0.0000332
AC:
2
AN:
60214
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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
AF:
0.0000328
AC:
5
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74376
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.555
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.0000664
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:5
Sep 19, 2016
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 17, 2023
Myriad Genetics, Inc.
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Jun 27, 2023
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The APC c.669A>C (p.Gln223His) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD non-cancer v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, however this prediction is not considered informative for missense variants affecting the APC gene. To our knowledge functional studies have not been performed and this variant has not been reported in individuals with APC-related familial adenomatous polyposis or attenuated familial adenomatous polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 223 of the APC protein (p.Gln223His). This variant is present in population databases (rs769482880, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of APC-related conditions (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 184601). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 08, 2024
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Sep 30, 2020
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Apr 03, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces glutamine with histidine at codon 223 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual being evaluated for familial adenomatous polyposis (PMID: 23159591). This variant has been identified in 4/251000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1
Nov 24, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: APC c.669A>C (p.Gln223His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251000 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.669A>C has been reported in the literature as a VUS in one individual undergoing testing for APC gene analysis (example, Kerr_2013). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3; likely benign, n=1). Most submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1
May 20, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals undergoing APC genetic testing (PMID: 23159591); This variant is associated with the following publications: (PMID: 27882345, 23159591) -

Classic or attenuated familial adenomatous polyposis Uncertain:1
Jun 26, 2023
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces glutamine with histidine at codon 223 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual being evaluated for familial adenomatous polyposis (PMID: 23159591). This variant has been identified in 4/251000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.18
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;D;T
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
.;D;D
M_CAP
Uncertain
0.29
D
MetaRNN
Pathogenic
0.76
D;D;D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Uncertain
2.8
M;M;.
PhyloP100
1.9
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.8
D;D;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0090
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.72
MutPred
0.20
Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP
0.92
ClinPred
0.94
D
GERP RS
5.2
Varity_R
0.47
gMVP
0.58
Mutation Taster
=37/63
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
Splicevardb
2.0
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs769482880; hg19: chr5-112128166; API