5-112840862-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000038.6(APC):c.5268T>G(p.Ser1756Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,613,728 control chromosomes in the GnomAD database, including 319,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1756S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.60 ( 28136 hom., cov: 32)

Exomes 𝑓: 0.63 ( 291657 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: 0.169

Publications

73 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 5-112840862-T-G is Benign according to our data. Variant chr5-112840862-T-G is described in ClinVar as Benign. ClinVar VariationId is 42245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.169 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.5268T>G	p.Ser1756Ser	synonymous_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.5268T>G	p.Ser1756Ser	synonymous_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 link	n.228+11890T>G		intron_variant	Intron 3 of 7	3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.603

AC:

91592

AN:

151940

Hom.:

28119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.535

Gnomad AMI

AF:

0.614

Gnomad AMR

AF:

0.669

Gnomad ASJ

AF:

0.574

Gnomad EAS

AF:

0.820

Gnomad SAS

AF:

0.731

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.615

Gnomad OTH

AF:

0.615

GnomAD2 exomes

AF:

0.651

AC:

163104

AN:

250444

AF XY:

0.651

show subpopulations

Gnomad AFR exome

AF:

0.534

Gnomad AMR exome

AF:

0.734

Gnomad ASJ exome

AF:

0.592

Gnomad EAS exome

AF:

0.821

Gnomad FIN exome

AF:

0.560

Gnomad NFE exome

AF:

0.621

Gnomad OTH exome

AF:

0.650

GnomAD4 exome

AF:

0.629

AC:

919568

AN:

1461670

Hom.:

291657

Cov.:

AF XY:

0.631

AC XY:

458889

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.521

AC:

17447

AN:

33470

American (AMR)

AF:

0.727

AC:

32521

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.591

AC:

15451

AN:

26134

East Asian (EAS)

AF:

0.840

AC:

33361

AN:

39698

South Asian (SAS)

AF:

0.710

AC:

61229

AN:

86250

European-Finnish (FIN)

AF:

0.574

AC:

30637

AN:

53402

Middle Eastern (MID)

AF:

0.616

AC:

3555

AN:

5768

European-Non Finnish (NFE)

AF:

0.618

AC:

687033

AN:

1111840

Other (OTH)

AF:

0.635

AC:

38334

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

22125

44249

66374

88498

110623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18574

37148

55722

74296

92870

<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:

0.603

AC:

91661

AN:

152058

Hom.:

28136

Cov.:

AF XY:

0.604

AC XY:

44907

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.535

AC:

22185

AN:

41450

American (AMR)

AF:

0.669

AC:

10226

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.574

AC:

1991

AN:

3468

East Asian (EAS)

AF:

0.819

AC:

4247

AN:

5184

South Asian (SAS)

AF:

0.731

AC:

3522

AN:

4820

European-Finnish (FIN)

AF:

0.536

AC:

5662

AN:

10556

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.615

AC:

41788

AN:

67984

Other (OTH)

AF:

0.613

AC:

1294

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1822

3644

5467

7289

9111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.608

Hom.:

38634

Bravo

AF:

0.611

Asia WGS

AF:

0.755

AC:

2622

AN:

3478

EpiCase

AF:

0.612

EpiControl

AF:

0.615

ClinVar

Significance: Benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Mar 01, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Mar 28, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2021

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 24, 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. -

Familial adenomatous polyposis 1

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 c.5268T>G, p.Ser1756Ser silent variant, located in exon 16 of APC, is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs_id: rs866006) with a heterozygosity freqency of 0.478+/-0.104. Based on the above information, this is a benign variant. -

APC-Associated Polyposis Disorders

Benign:1

Jan 12, 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. -

Familial colorectal cancer

Other:1

Systems Biology Platform Zhejiang California International NanoSystems Institute

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.24

(source)

DANN

Benign

0.52

PhyloP100

0.17

Mutation Taster

=98/2

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