NM_000038.6:c.835-7T>G

Variant names:

• chr5-112815488-T-G
• rs1554079128
• NM_000038.6:c.835-7T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3 PS3_Moderate PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.835-7T>G variant in APC is an intronic variant in intron 8. This variant has been reported in 3 families meeting phenotypic criteria, resulting in a total phenotype score of 2.5 (PS4_Moderate, PMID:18433509, internal data Labcorp Genetics (formerly Invitae)). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEnt) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 8 and creating a cryptic acceptor splice site (PP3). RT-PCR sequencing of cDNA demonstrated that the variant impacts splicing by insertion of the last six bases of intron 8 between exon 8 and 9, the second inserted codon is a stop codon. However, relative quantitation of full-length normal transcript versus mutant was not performed (PS3_Moderate, PMID 18433509). In summary, this variant is a Likely Pathogenic variant for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS4_Moderate, PS3_Moderate, PM2_Supporting and PP3 applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA645372415/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 0.495
• Publications: 1 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• PP3: 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.835-7T>G		splice_region_variant, intron_variant	Intron 8 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.835-7T>G		splice_region_variant, intron_variant	Intron 8 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Apr 27, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18433509, 20649969, Myriad internal data].

Sep 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 18433509). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 433614). This variant has been observed in individuals with familial adenomatous polyposis (PMID: 18433509; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the APC gene. It does not directly 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 disrupted protein product.

May 15, 2025

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000038.6(APC):c.835-7T>G variant in APC is an intronic variant in intron 8. This variant has been reported in 3 families meeting phenotypic criteria, resulting in a total phenotype score of 2.5 (PS4_Moderate, PMID: 18433509, internal data Labcorp Genetics (formerly Invitae)). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEnt) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 8 and creating a cryptic acceptor splice site (PP3). RT-PCR sequencing of cDNA demonstrated that the variant impacts splicing by insertion of the last six bases of intron 8 between exon 8 and 9, the second inserted codon is a stop codon. However, relative quantitation of full-length normal transcript versus mutant was not performed (PS3_Moderate, PMID 18433509). In summary, this variant is a Likely Pathogenic variant for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS4_Moderate, PS3_Moderate, PM2_Supporting and PP3 applied (VCEP specifications version v2.1.0; date of approval 11/24/2023).

not provided Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APC c.835-7T>G variant was identified in 1 of 192 proband chromosomes (frequency 0.005) from individuals with familial adenomatous polyposis (FAP) (Kanter-Smoler 2008) and was also identified in the HGMD and the “InSIGHT Colon Cancer Databases”. The variant was not identified in dbSNP, Clinvitae database COSMIC, Zhejiang Colon Cancer Database (LOVD), ClinVar database, Clinvitae, GeneInsight-COGR databases, UMD, The NHLBI GO Exome Sequencing Project, the genome aggregation consortium (Feb 27, 2017), and the Exome Aggregation Consortium database (August 8, 2016). The variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing, with 4 of 5 different programs predicting the abolishment of the known splicing acceptor site at nucleotide position c.835, and 2 of 5 predicting the creation of a splicing acceptor site at the position of the variant, c.835-7. Additionally, Kanter-Smoler (2008) detected an aberrant APC polypeptide pattern produced by this variant in an RNA-based protein truncation test. The authors of this study suggest that this base substitution introduces a new splice acceptor site which is apparently preferred by the splicing machinery and results in the inclusion of the last six bases of intron 10 (alias exon 7) causing a frameshift, which alters the protein's amino acid sequence and results in a premature termination codon downstream. 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 pathogenic role for this variant. This variant is classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.81
PhyloP100		0.49
Mutation Taster		=29/71	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 1
DS_AL_spliceai		0.73		Position offset: 7

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

Other links and lift over

dbSNP: rs1554079128; hg19: chr5-112151185; COSMIC: COSV104439186;