5-112835163-C-T

Variant names:

• chr5-112835163-C-T
• rs1064793716
• NM_000038.6:c.1956C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2_Supporting PS4_Supporting PS3

This summary comes from the ClinGen Evidence Repository: The c.1956C>T variant in APC is predicted to be a synonymous (silent) variant (p.His652=). It is located at the third-last nucleotide of exon 15. Two RNA based RT-PCR assays demonstrate out-of-frame skipping of exon 15, with evidence that the variant allele produces <10% of the full-length transcript (PS3; PMID:15459959, 22987206). This variant has been reported in 3 probands meeting least 1.5 phenotype points (PS4_Supporting; PMID:15459959, 22987206). The variant is not reported in gnomAD (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3, PS4_Supporting and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16618077/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.9730
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 2.54
• Publications: 5 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_pathogenic. The variant received 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.1956C>T	p.His652His	splice_region synonymous	Exon 15 of 16	NP_000029.2
	APC	NM_001407446.1		c.2040C>T	p.His680His	splice_region synonymous	Exon 15 of 16	NP_001394375.1
	APC	NM_001354896.2		c.2010C>T	p.His670His	splice_region synonymous	Exon 16 of 17	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.1956C>T	p.His652His	splice_region synonymous	Exon 15 of 16	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.1956C>T	p.His652His	splice_region synonymous	Exon 16 of 17	ENSP00000427089.2
	APC	ENST00000502371.3	TSL:1	n.*154C>T		splice_region non_coding_transcript_exon	Exon 11 of 12	ENSP00000484935.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Feb 25, 2023

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1956C>T variant in APC is predicted to be a synonymous (silent) variant (p.His652=). It is located at the third-last nucleotide of exon 15. Two RNA based RT-PCR assays demonstrate out-of-frame skipping of exon 15, with evidence that the variant allele produces <10% of the full-length transcript (PS3; PMID: 15459959, 22987206). This variant has been reported in 3 probands meeting least 1.5 phenotype points (PS4_Supporting; PMID: 15459959, 22987206). The variant is not reported in gnomAD (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3, PS4_Supporting and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 652 of the APC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the APC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial adenomatous polyposis (FAP) (PMID: 15459959, 22987206; internal data). ClinVar contains an entry for this variant (Variation ID: 419202). Studies have shown that this variant results in skipping of exon 15 (also called exon 14), and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15459959, 22987206; internal data). For these reasons, this variant has been classified as Pathogenic.

Carcinoma of colon Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APC p.His652His variant was identified in 2 of 2512 proband chromosomes (frequency: 0.001) from German and Czech individuals or families with FAP/AFAP (Friedl 2005, Schwarzova 2013). Aretz et al (2004) were first to show this silent variant resulted in exon 14 skipping similar to substitutions at highly conserved splice acceptor and donor sites, versus the alternative splicing nature of exon 14 seen in normal controls, which was contrary to calls made by splice prediction models. This finding was also seen by Schwarzova (2013), in a patient with AFAP, who by RNA based RT-PCR analysis was shown to have the same or higher amounts of the mutant transcript in his blood, healthy colon and polyp tissue, compared to the blood and colon mucosa of healthy individuals. The variant was not identified in dbSNP, 1000 Genomes Project, NHLBI GO Exome Sequencing Project , the Exome Aggregation Consortium database, Clinvitae database, Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database, and UMD; but was identified in COSMIC (1x in an adenomacarcinoma of the large intestine, with somatic status) and in InSiGHT Colon Cancer Gene Variant Database (LOVD) (2x as a pathogenic germline mutation, in a classical FAP phenotype, and one unknown phenotype). The c.1956C>T variant occurs in the third last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. Two of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference in splicing and functional studies have demonstrated a splicing defect contradicting, increasing the likelihood this variant has clinical significance. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

not provided Pathogenic:1

Jun 24, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21078199, 9298819, 22987206, 19196998, 20223039, 21134075, 15459959, 35477782)

Hereditary cancer-predisposing syndrome Pathogenic:1

May 26, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1956C>T pathogenic variant (also known as p.H652H), located in coding exon 14 of the APC gene, results from a C to T substitution at nucleotide position 1956. This nucleotide substitution does not change the amino acid at codon 652. This variant has been reported in multiple individuals with familial adenomatous polyposis (Ambry internal data; Aretz S et al. Hum. Mutat. 2004 Nov;24(5):370-80; Schwarzov&aacute; L et al. Fam. Cancer 2013 Mar;12(1):35-42). This nucleotide position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis for this alteration is inconclusive. However, multiple RNA analyses have shown that this variant leads to substantial exon 14 skipping (Ambry internal data; Aretz S et al. 2004; Schwarzov&aacute; L et al. 2013). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.94
PhyloP100		2.5
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1064793716; hg19: chr5-112170860;