chr5-112840359-C-G

Variant names:

• chr5-112840359-C-G
• rs72541813
• NM_000038.6:c.4765C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP6

The NM_000038.6(APC):​c.4765C>G​(p.Arg1589Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000836 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1589C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:6 O:1
• Conservation: PhyloP100: 3.54
• Publications: 12 publications found

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

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 37 uncertain in NM_000038.6
• BP6: Variant 5-112840359-C-G is Benign according to our data. Variant chr5-112840359-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142201.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.4765C>G	p.Arg1589Gly	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.4765C>G	p.Arg1589Gly	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+11387C>G		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000677 AC: 17 AN: 251116 AF XY: 0.0000810

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000882 AC: 129 AN: 1461872 Hom.: 0 Cov.: 66 AF XY: 0.0000811 AC XY: 59 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000110 AC: 122 AN: 1111996

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74316

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.00011 (14/128838 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with thyroid cancer (PMID: 29684080 (2018)) and colorectal polyps (PMID: 22773231 (2013)), as well as healthy individuals (PMIDs: 18199528 (2008) and 30267214 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Mar 27, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with multiple adenomatous colon polyps, colorectal cancer, and other cancers, as well as in unaffected control participants from a study of colorectal cancer/polyposis (PMID: 30267214, 22773231, 27498913, 29684080, 36356413); This variant is associated with the following publications: (PMID: 18199528, 27498913, 22773231, 27156442, 29684080, 30122538, 36356413, 30267214) -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Mar 20, 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. -

Dec 05, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 11, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP1 c.4765C>G, located in exon 16 of the APC gene, is predicted to result in the substitution of Arg by Gly at codon 1589, p.(Arg1589Gly) (BP1).The variant allele was found in 12/117822 alleles, with a filter allele frequency of 0.006% at 95% confidence, within the European non-Finnish population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). The SpliceAI algorithm predicts no significant impact on splicing. To our knowledge, functional studies have not been reported for this variant. At present ClinVar does not describe pathogenic or likely pathogenic missense variants in this codon. This variant has been reported in individuals affected with multiple colorectal adenomas (PMIDs: 22773231, 36356413). This variant has been reported in ClinVar database (4x likely benign, 12x uncertain significance), but it is not present in the LOVD database. Based on currently available information, the variant c.4765C>G should be considered a likely benign variant. -

Mar 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glycine at codon 1589 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with multiple colorectal adenomas (PMID: 22773231), thyroid cancer (PMID: 29684080), and sarcoma (PMID: 27498913), but also in control individuals (PMID: 18199528, 30267214). This variant has been identified in 19/282472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:2 Benign:1

Apr 16, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the APC gene demonstrated a sequence change, c.4765C>G, in exon 16 that results in an amino acid change, p.Arg1589Gly. This sequence change does not appear to have been previously described in patients with APC-related disorders and has been described in the gnomAD database with a low population frequency of 0.0067% (dbSNP rs72541813). The p.Arg1589Gly change affects a moderately conserved amino acid residue located in a domain of the APC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1589Gly substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1589Gly change remains unknown at this time. -

Jul 06, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APC c.4765C>G (p.Arg1589Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251116 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in APC causing Familial Adenomatous Polyposis (6.8e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.4765C>G has been reported in the literature in individuals affected with a personal or family history of colorectal polyposis without strong evidence of causality (Poliani_2022, Urso_2013). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36356413, 22773231). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=9) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 1 Uncertain:1 Benign:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 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 in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -

Oct 26, 2016

Counsyl

Significance: Uncertain significance

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. -

APC-Associated Polyposis Disorders Uncertain:1 Other:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Likely benign and reported on 11-14-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Classic or attenuated familial adenomatous polyposis Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glycine at codon 1589 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with multiple colorectal adenomas (PMID: 22773231), thyroid cancer (PMID: 29684080), and sarcoma (PMID: 27498913), but also in control individuals (PMID: 18199528, 30267214). This variant has been identified in 19/282472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Gastric cancer Uncertain:1

May 02, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diffuse midline glioma, H3 K27-altered Uncertain:1

May 16, 2022

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary cancer Benign:1

Jan 23, 2024

Mendelics

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	0.21
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D
Eigen	Benign	0.088
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.9	L;L
PhyloP100		3.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.72	P;P
Vest4		0.37
MVP		0.86
ClinPred		0.16	T
GERP RS		5.3
Varity_R		0.57
gMVP		0.56
Mutation Taster		=51/49	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

Other links and lift over

dbSNP: rs72541813; hg19: chr5-112176056;