5-112840884-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000038.6(APC):c.5290C>G(p.Gln1764Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. Q1764H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 2.89

Publications

3 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

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09004566).

BP6

Variant 5-112840884-C-G is Benign according to our data. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021. Variant chr5-112840884-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141021.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.5290C>G	p.Gln1764Glu	missense_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 link	c.5290C>G	p.Gln1764Glu	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 link	n.228+11912C>G		intron_variant	Intron 3 of 7	3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

250532

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:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461570

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111738

Other (OTH)

AF:

0.0000331

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41544

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:3Benign:1

Jan 29, 2025

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Sep 26, 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. -

Aug 25, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 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 glutamic acid, which is acidic and polar, at codon 1764 of the APC protein (p.Gln1764Glu). This variant is present in population databases (rs529543591, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 141021). 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) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome

Benign:2

Jul 14, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Mar 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer

Uncertain:1

May 21, 2018

3DMed Clinical Laboratory Inc

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1

Oct 10, 2023

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 does not alter protein structure/function; Observed in individuals with breast cancer (Chen et al., 2020); This variant is associated with the following publications: (PMID: 32091409, 18199528) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.36

T;T

Eigen

Benign

-0.041

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.090

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.81

L;L

PhyloP100

2.9

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.27

Sift

Uncertain

0.018

D;D

Sift4G

Benign

1.0

T;T

Polyphen

0.094

B;B

Vest4

0.40

MutPred

0.11

Loss of MoRF binding (P = 0.0234);Loss of MoRF binding (P = 0.0234);

MVP

0.80

ClinPred

0.13

GERP RS

6.2

Varity_R

0.10

gMVP

0.40

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over