5-112843456-C-G

Variant names:

• chr5-112843456-C-G
• rs72541816
• NM_000038.6:c.7862C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2 BA1 BP1

This summary comes from the ClinGen Evidence Repository: The c.7862C>G variant in APC is a missense variant predicted to cause the substitution of Serine by Cysteine at amino acid position 2621 (p.Ser2621Cys). This variant has been observed in more than 10 heterozygous individuals over the age of 50 with no features of FAP, worth more than 10 healthy individual points (BS2; Ambry internal data). APC is defined by the ClinGen APC VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.5021% in the non-Finnish European population, which is higher than the ClinGen APC VCEP threshold of 0.1% for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BA1, BS2, and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA014123/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (22 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign reviewed by expert panel B:24 O:1
• Conservation: PhyloP100: 4.73

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]

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.7862C>G	p.Ser2621Cys	missense_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.7862C>G	p.Ser2621Cys	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.229-13193C>G		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152174 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00551

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00291 AC: 727 AN: 249960 AF XY: 0.00290

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00505

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00475 AC: 6949 AN: 1461508 Hom.: 22 Cov.: 34 AF XY: 0.00468 AC XY: 3401 AN XY: 727070

African (AFR) AF: 0.000777 AC: 26 AN: 33464

American (AMR) AF: 0.000738 AC: 33 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00229 AC: 197 AN: 86198

European-Finnish (FIN) AF: 0.00197 AC: 105 AN: 53418

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.00572 AC: 6356 AN: 1111754

Other (OTH) AF: 0.00348 AC: 210 AN: 60382

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152292 Hom.: 3 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74468

African (AFR) AF: 0.00132 AC: 55 AN: 41562

American (AMR) AF: 0.00216 AC: 33 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00551 AC: 375 AN: 68020

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00460 Hom.: 2

Bravo AF: 0.00320

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00312 AC: 379

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00451

ClinVar

Significance: Benign

Submissions summary: Benign:24 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:7

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APC: BP4, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24728327, 27153395, 1316610, 24082139, 21859464, 24599579, 25260786, 22703879) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:5 Other:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Oct 16, 2019

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

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

- -

Sep 30, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 1 Benign:5

Feb 26, 2023

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.7862C>G variant in APC is a missense variant predicted to cause the substitution of Serine by Cysteine at amino acid position 2621 (p.Ser2621Cys). This variant has been observed in more than 10 heterozygous individuals over the age of 50 with no features of FAP, worth more than 10 healthy individual points (BS2; Ambry internal data). APC is defined by the ClinGen APC VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.5021% in the non-Finnish European population, which is higher than the ClinGen APC VCEP threshold of 0.1% for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BA1, BS2, and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 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. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5

Nov 28, 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. -

Aug 04, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 21, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

APC-Associated Polyposis Disorders Benign:1

Mar 06, 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.Ser2621Cys variant has been previously reported in the literature. From selected publications it was identified in 7 if 2428 case chromosomes (frequency: 0.0028) and 21 of 3670 control chromosomes (frequency: 0.0057), increasing the likelihood this is a benign polymorphism (Miyoshi_1992_1316610, Scott_2004_2839999, Ruiz-Ponte_2001_11668620, Azzopardi_2008_18199528, Lefevre_2012_22875147). In addition, it is reported with a frequency of 126/2172 control chromosomes from the 1000 genomes project and at a frequency of 0.005 in the European gohort ESP project database (dbSNPiD: rs72541816). Furthermore, 2 studies demonstrated non-segregation (Scott_2004_2839999, Ruiz-Ponte_2001_11668620) and the frequency of this variant was reported as higher in controls vs cases in two studies (Cancer Res-2008-Azzopardi-358-63_18199528, Lefevre_2012_jhg201299a_22875147), increasing the likelihood that this variant is benign. This variant is conserved in mammals but not lower organisms although it appears to not be located in an important functional domain, the creation of cystein residues, having a higher propensity for generating disulphide bonds, could in theory impact the protein. Computational analysis using several programs (SIFT, AlignGVGD, Polyphen-2, BLOSUM), do not agree on the imapact this variant change may have, and this information is not very predictive of pathogenicity. Based on the above information, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Uncertain	0.52	D;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.86	.;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		4.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.90	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.64	P;P
Vest4		0.30
MVP		0.74
ClinPred		0.014	T
GERP RS		6.1
Varity_R		0.075
gMVP		0.50
Mutation Taster		=96/4	polymorphism

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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Other links and lift over

dbSNP: rs72541816; hg19: chr5-112179153; COSMIC: COSV99078827; COSMIC: COSV99078827;