5-112839543-G-C

Variant names:

• chr5-112839543-G-C
• rs1801166
• NM_000038.6:c.3949G>C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000038.6(APC):​c.3949G>C​(p.Glu1317Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00727 in 1,614,214 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. E1317G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0055 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (54 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:25 O:2
• Conservation: PhyloP100: 4.69

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

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 15 uncertain in NM_000038.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.00723657).
• BP6: Variant 5-112839543-G-C is Benign according to our data. Variant chr5-112839543-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839543-G-C is described in Lovd as [Benign]. Variant chr5-112839543-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00554 (844/152344) while in subpopulation NFE AF= 0.00739 (503/68028). AF 95% confidence interval is 0.00686. There are 6 homozygotes in gnomad4. There are 363 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 844 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.3949G>C	p.Glu1317Gln	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.3949G>C	p.Glu1317Gln	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+10571G>C		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.00554 AC: 843 AN: 152226 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00574

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00739

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00438 AC: 1101 AN: 251162 Hom.: 8 AF XY: 0.00443 AC XY: 601 AN XY: 135724

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00646

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00745 AC: 10894 AN: 1461870 Hom.: 54 Cov.: 33 AF XY: 0.00720 AC XY: 5236 AN XY: 727238

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00197

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00863

Gnomad4 OTH exome AF: 0.00864

GnomAD4 genome AF: 0.00554 AC: 844 AN: 152344 Hom.: 6 Cov.: 32 AF XY: 0.00487 AC XY: 363 AN XY: 74488

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00739

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00688 Hom.: 3

Bravo AF: 0.00597

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00636 AC: 28

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00413 AC: 501

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00736

EpiControl AF: 0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:25 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1 Benign:6 Other:1

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 18, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2014

Pathway Genomics

Significance: Likely benign

Review Status: no assertion criteria provided

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. -

Sep 22, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Benign:6 Other:1

Jul 01, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu1317Gln variant in APC is classified as benign because of lack of conservation and it has been identified in 0.63% (810/128934, 7 homozygotes) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). While variant is present in >12 papers comments suggesting non-pathogenicity. ACMG/AMP Criteria applied: BA1, BP4. -

-

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 10, 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. -

Dec 03, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:6

Jul 21, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: 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 -

Nov 03, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Benign:5

Aug 11, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 02, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2019

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. -

Jul 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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.Glu1317Gln variant has been previously identified in the literature in 43/4470 (0.010) proband chromosomes and in 26/5002 (0.005) control chromosomes suggesting that this variant is a common variant observed 2 fold higher frequency in probands with attenuated FAP, FAP or multiple adenomas compared to controls (Aceto 2005, Curia 2012, Frayling 1998, Lamlum 2000, Plawski 2008, Azzopardi 2008, Hahnloser 2003, Liang 2013, Abdel-Malak 2015). One study demonstrated loss of heterozygosity in the colon cancer tumors in two individuals from the same family both retaining the variant, however segregation of this variant was not observed in two others with colorectal cancer in the same family and the although the family had multiple members affected with colon cancer their phenotypes were not consistent with FAP (White 1996). Further studies suggested the germline p.Glu1317Gln variant may provide a growth advantage for colorectal tumorigenesis when in combination with other weak mutant APC alleles (Dallosso 2009), but does not account for the occurrence of adenomas (Olschwang 2009 ). While some studies have suggested that the non-synonymous variant p.Glu1317Gln predisposes to multiple colorectal adenomas and CRCs (Lamlum 2000, Hahnloser 2003, Frayling 1998), other studies support a moderate increase in risk of CRC, or none ( Popat 2000, Zauber 2013, Rozek 2006). rnThe variant was identified in dbSNP (ID: rs1801166) “With other allele”, Clinvitae database (classified as benign and conflicting interpretations), COSMIC (in various tissues other than intestinal), InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database (classifications: benign by Invitae, GeneDX, Emory Genetics, Biesecker Laboratory; uncertain significance by Mayo Clinic and Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine; pathogenic by OMIM and GeneReviews; and classification not provided by ITMI), GeneInsight - COGR database (classified as uncertain significance by a clinical laboratory), and UMD (5x with a “neutral” classification). The variant was identified by our laboratory in 6 individuals with colon or other cancers. The variant was identified in the 1000 Genomes Project in 15 of 5000 chromosomes (frequency: 0.003); HAPMAP-EUR in 6 of 1006 chromosomes (frequency: 0.006), HAPMAP-AFR in 4 of 1322 chromosomes (frequency: 0.003), HAPMAP-SAS in 3 of 978 chromosomes (frequency: 0.003); NHLBI Exome Sequencing Project (ESP) in 80 of 8600 European American (frequency 0.009) and in 28 of 4400 African American alleles (frequency 0.006); the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 500 of 121152 chromosomes (frequency: 0.0.004) (or 382 European individuals, 6 of which are homozygotes, 48 African, 4 Other, 32 Latino, 31 South Asian, 3 European (Finnish), increasing the likelihood this could be a low frequency benign variant. In addition we have observed this variant co-occuring with a known pathogenic variant (APC, c.3183_3187delACAAA) in a patient with confirmed FAP. The p.Glu1317 residue is mostly conserved in mammals with the variant amino acid Gln present in rat, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein, increasing the likelihood that this variant does not have clinical significance; however, this information is not predictive enough to rule out 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 benign. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Uncertain	0.56	D;D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.052
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	.;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0072	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.21
Sift	Benign	0.15	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0010	B;B
Vest4		0.14
MVP		0.76
ClinPred		0.022	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs1801166; hg19: chr5-112175240; COSMIC: COSV57322109; COSMIC: COSV57322109;