chr5-112842120-T-C

Variant names:

• chr5-112842120-T-C
• rs183468041
• NM_000038.6:c.6526T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000038.6(APC):​c.6526T>C​(p.Leu2176Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,610,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L2176L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17
• Conservation: PhyloP100: 0.668
• Publications: 6 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-112842120-T-C is Benign according to our data. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779. Variant chr5-112842120-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181779.
• BP7: Synonymous conserved (PhyloP=0.668 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.6526T>C	p.Leu2176Leu	synonymous_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.6526T>C	p.Leu2176Leu	synonymous_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+13148T>C		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000245 AC: 61 AN: 248880 AF XY: 0.000252

Gnomad AFR exome AF: 0.0000642

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000182 AC: 266 AN: 1458968 Hom.: 0 Cov.: 34 AF XY: 0.000183 AC XY: 133 AN XY: 725886

African (AFR) AF: 0.0000301 AC: 1 AN: 33212

American (AMR) AF: 0.000383 AC: 17 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 49 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 85898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000159 AC: 176 AN: 1110238

Other (OTH) AF: 0.000382 AC: 23 AN: 60246

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74300

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.000131 AC: 2 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67966

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000281 Hom.: 0

Bravo AF: 0.000264

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Jan 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 08, 2016

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APC: BP4, BP7 -

May 09, 2016

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.6526T>C (p.Leu2176Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a damaging outcome for this variant. This variant was found in 24/119852 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.0005199 (6/11540). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000602), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Clinical diagnostic laboratories classified this variant as Benign/Likely Benign. Taken together, this variant is classified as Benign. -

Hereditary cancer-predisposing syndrome Benign:4

Feb 20, 2024

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2014

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 17, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 16, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2014

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. -

Jul 13, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 1 Benign:3

Apr 05, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

APC-Associated Polyposis Disorders Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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.Leu2176= variant was not identified in the literature nor was it identified in the GeneInsight, Cosmic, UMD and Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs183468041) “With unknown allele”, with a minor allele frequency of 0.0002 (1 of 5000 chromosomes in 1000 Genomes Project). In the NHLBI Exome Sequencing Project (Exome Variant Server), the variant was identified in 1 of 8590 European American chromosomes and was not found in 4390 African American chromosomes. In Exome Aggregation Consortium (ExAC) database, the variant was identified in 17 of 6605 European (Non-Finnish), 6 of 11540 Latinos and 1 of 9654 Africans, increasing the likelihood this could be a low frequency benign variant in certain populations of origin. The variant was identified in Clinvitae (1x as variant of unknown significance), LOVD (1x as no known pathogenicity) and InSiGHT Colon Cancer Database. In the ClinVar database the variant was reported as benign by GeneDX and as likely benign by Ambry Genetics. The p.Leu2176= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.1
DANN	Benign	0.82
PhyloP100		0.67
Mutation Taster		=95/5	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: rs183468041; hg19: chr5-112177817; COSMIC: COSV57348230;