rs2229995

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000038.6(APC):c.7504G>A(p.Gly2502Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0199 in 1,613,962 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2502D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 40 hom., cov: 32)

Exomes 𝑓: 0.020 ( 372 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:23O:1

Conservation

PhyloP100: 4.02

Publications

55 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006817907).

BP6

Variant 5-112843098-G-A is Benign according to our data. Variant chr5-112843098-G-A is described in ClinVar as Benign. ClinVar VariationId is 41514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.017 (2589/152258) while in subpopulation SAS AF = 0.0246 (119/4828). AF 95% confidence interval is 0.0217. There are 40 homozygotes in GnomAd4. There are 1335 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.7504G>A	p.Gly2502Ser	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.7504G>A	p.Gly2502Ser	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 link	n.229-13551G>A		intron_variant	Intron 3 of 7	3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2589

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00430

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0244

Gnomad FIN

AF:

0.0402

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0227

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.0197

AC:

4951

AN:

251266

AF XY:

0.0206

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.00793

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0422

Gnomad NFE exome

AF:

0.0231

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0203

AC:

29606

AN:

1461704

Hom.:

372

Cov.:

AF XY:

0.0205

AC XY:

14934

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.00272

AC:

AN:

33474

American (AMR)

AF:

0.00836

AC:

374

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

271

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.0265

AC:

2288

AN:

86248

European-Finnish (FIN)

AF:

0.0393

AC:

2101

AN:

53416

Middle Eastern (MID)

AF:

0.0189

AC:

109

AN:

5768

European-Non Finnish (NFE)

AF:

0.0208

AC:

23133

AN:

1111858

Other (OTH)

AF:

0.0205

AC:

1236

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1819

3638

5458

7277

9096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.0170

AC:

2589

AN:

152258

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1335

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00428

AC:

178

AN:

41554

American (AMR)

AF:

0.0150

AC:

229

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0246

AC:

119

AN:

4828

European-Finnish (FIN)

AF:

0.0402

AC:

426

AN:

10602

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0227

AC:

1542

AN:

68012

Other (OTH)

AF:

0.0137

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

132

263

395

526

658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0194

Hom.:

135

Bravo

AF:

0.0137

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0200

AC:

172

ExAC

AF:

0.0198

AC:

2410

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0204

EpiControl

AF:

0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 14, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 22, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:5

Nov 18, 2014

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 27, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 20, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Oct 10, 2017

True Health Diagnostics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 08, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial adenomatous polyposis 1

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 10, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Nov 24, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

APC: BP4, BS1, BS2 -

Familial multiple polyposis syndrome

Benign:1

Aug 07, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

APC-Associated Polyposis Disorders

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Carcinoma of colon

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The p.Gly2502Ser variant was previously identified in the literature in 138 of 6866 proband chromosomes (frequency 0.020) from individuals with adenoma or colorectal cancer and in 157 of 8192 control chromosomes (frequency 0.019) from healthy individuals (Cleary 2008, Hadjisavvas 2006, Miyoshi 1992, Scott 2004, Tranah 2005, Wong 2010, Zhou 2004). This variant was also identified in the dbSNP (ID#rs2229995), HGMD, and LOVD databases, and was reported in several populations including the ESP Project with a frequency of 0.020 in European American alleles, the 1000 Genomes Project with a frequency of 0.010, and HapMap-CEU with a frequency of 0.032. The p.Gly2502 residue is not conserved through evolution and the variant (Ser) is found at this position in chicken and fruitfly, increasing the likelihood that this is a benign variant. In addition, Tranah (2005) found that this variant was not associated with risk of colorectal cancer or adenoma in men and women, and Zhou (2004) did not observe segregation of this variant with disease. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-0.042

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.90

.;D

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-0.29

N;N

PhyloP100

4.0

PrimateAI

Benign

0.37

PROVEAN

Benign

0.030

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.30

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.15

B;B

Vest4

0.12

ClinPred

0.0096

GERP RS

6.0

Varity_R

0.060

gMVP

0.36

Mutation Taster

=90/10

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over