NM_000038.6:c.423-9A>G

Variant names:

• chr5-112775620-A-G
• rs1554071494
• NM_000038.6:c.423-9A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PS3_Moderate PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.423-9A>G variant in APC is an intronic variant which is localized in intron 4. This variant has been reported in 2 families meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate, internal data Labcorp Genetics (formerly Invitae)). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (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, MaxEntScan, VarSeak) indicate that this variant may affect splicing by creating a new acceptor splice site and disrupting the native acceptor splice site of intron 4 of APC, resulting in the insertion of the 8 last bp of intron 4 (PP3). RT-PCR and mini-gene demonstrated that the variant impacts splicing by insertion of the last 8 bp of intron 4 resulting in a premature stop codon (PS3_Moderate, PMID:24599579). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS3_Moderate, PS4_Moderate, PM2_Supporting, PP3 (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA658657473/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 intron
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: -1.23
• Publications: 0 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 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.
• PP3: 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.423-9A>G		intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.453-9A>G		intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.423-9A>G		intron	N/A	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.423-9A>G		intron	N/A	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.423-9A>G		intron	N/A	ENSP00000427089.2
	APC	ENST00000502371.3	TSL:1	n.423-9A>G		intron	N/A	ENSP00000484935.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

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 26, 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: 24599579, Myriad internal data].

Dec 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 469955). This variant has been observed in individuals with familial adenomatous polyposis (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein.

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.423-9A>G variant in APC is an intronic variant which is localized in intron 4. This variant has been reported in 2 families meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate, internal data Labcorp Genetics (formerly Invitae)). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (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, MaxEntScan, VarSeak) indicate that this variant may affect splicing by creating a new acceptor splice site and disrupting the native acceptor splice site of intron 4 of APC, resulting in the insertion of the 8 last bp of intron 4 (PP3). RT-PCR and mini-gene demonstrated that the variant impacts splicing by insertion of the last 8 bp of intron 4 resulting in a premature stop codon (PS3_Moderate, PMID: 24599579). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS3_Moderate, PS4_Moderate, PM2_Supporting, PP3 (VCEP specifications version v2.1.0; date of approval 11/24/2023).

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 12, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.423-9A>G intronic pathogenic mutation results from an A to G substitution 9 nucleotides upstream from coding exon 4 in the APC gene. This variant has been observed in individuals with a personal and/or family history that is consistent with APC-associated disease (Ambry internal data; External communication; Grandval P et al. Hum Mutat 2014 May;35(5):532-6.). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Grandval P et al. Hum Mutat 2014 May;35(5):532-6.). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.6
DANN	Benign	0.63
PhyloP100		-1.2
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 1
DS_AL_spliceai		0.77		Position offset: 9

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

Other links and lift over

dbSNP: rs1554071494; hg19: chr5-112111317;