5-112838180-C-G

Variant names:

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.2586C>G(p.Asn862Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,614,184 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N862S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 3 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.895

Publications

13 publications found

Variant links:

COSMIC-nc: COSV57340272

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=0.008746684).

BP6

Variant 5-112838180-C-G is Benign according to our data. Variant chr5-112838180-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000255 (373/1461878) while in subpopulation SAS AF = 0.00292 (252/86258). AF 95% confidence interval is 0.00262. There are 3 homozygotes in GnomAdExome4. There are 254 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.2586C>G	p.Asn862Lys	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.2586C>G	p.Asn862Lys	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 link	n.228+9208C>G		intron_variant	Intron 3 of 7	3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000398

AC:

100

AN:

251070

AF XY:

0.000538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000255

AC:

373

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

254

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00292

AC:

252

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000764

AC:

AN:

1112008

Other (OTH)

AF:

0.000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000158

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000453

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 15, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The APC c.2586C>G (p.Asn862Lys) variant involves the alteration of a conserved nucleotide and 2/3 in silico tools (Mutation Taster and SNPsandGo not captured here due to low p-value and reliability index value, respectively) predict a benign outcome. However, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 55/121326 (1/2206), predominantly in the South Asian cohort, 44/16508 (1/375), which does exceed the estimated maximal expected allele frequency for a pathogenic APC variant of 1/14005/ Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of South Asian origin. Multiple publications have cited the variant in affected individuals, although with limited information (ie, lack of cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. -

Sep 28, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327, 25980754, 27156442, 27882345) -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 08, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

APC: BS1 -

Familial adenomatous polyposis 1

Benign:4

Apr 05, 2018

Counsyl

Significance:Likely benign

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. -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2023

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Sep 14, 2018

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. -

Jun 20, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely 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:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The APC p.Asn862Lys variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs147972247) as "With Likely benign allele", ClinVar (classified as benign by Invitae and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Ambry Genetics and three other submitters), Cosmic (1x in large intestine tissue), and LOVD 3.0 (1x likely benign). The variant was not identified in COGR, MutDB, UMD-LSDB, or Zhejiang University databases. The variant was identified in control databases in 103 of 276786 chromosomes at a frequency of 0.0004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 82 of 30778 chromosomes (freq: 0.003), Other in 3 of 6458 chromosomes (freq: 0.0005), European in 16 of 126320 chromosomes (freq: 0.0001), and Latino in 2 of 34414 chromosomes (freq: 0.00006); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asn862 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

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. -

Classic or attenuated familial adenomatous polyposis

Benign:1

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Uncertain

0.49

.;T;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.87

D;.;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.0087

T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.34

.;N;N;.

PhyloP100

0.90

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.060

N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.71

T;T;T;T

Sift4G

Benign

0.72

T;T;T;T

Polyphen

0.0030

.;B;B;.

Vest4

0.14, 0.11

MutPred

0.21

.;Gain of ubiquitination at N862 (P = 0.0048);Gain of ubiquitination at N862 (P = 0.0048);Gain of ubiquitination at N862 (P = 0.0048);

MVP

0.76

ClinPred

0.0056

GERP RS

2.0

Varity_R

0.035

gMVP

0.18

Mutation Taster

=82/18

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over