chr5-112819347-A-C

Variant names:

• chr5-112819347-A-C
• rs863225311
• NM_000038.6:c.1312+3A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PS1 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.1312+3A>C variant in APC is an intronic variant, which is located at the 3rd nucleotide in intron 10. This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 2 points (PS4_Moderate, Ambry Genetics internal data, Tsukanov et al 2017; Russian Journal of Genetics, 2017, Vol. 53, No. 3, pp. 369–375). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from two in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 10 of APC (PP3). Moreover, this variant has similar in silico predictions compared to another noncanonical splicing variant at that same nucleotide position (c.1312+3A>G) (ClinVar ID: 217924), which is classified as pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) (PS1). 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 HCCP VCEP: criteria PS1, PM2_Supporting, PP3, and PS4_Moderate applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA658655920/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 5.88
• Publications: 3 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 8 ACMG points.

• PS1: 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.1312+3A>C		splice_region_variant, intron_variant	Intron 10 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1312+3A>C		splice_region_variant, intron_variant	Intron 10 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1

May 16, 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.1312+3A>C variant in APC is an intronic variant, which is located at the 3rd nucleotide in intron 10. This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 2 points (PS4_Moderate, Ambry Genetics internal data, Tsukanov et al 2017; Russian Journal of Genetics, 2017, Vol. 53, No. 3, pp. 369–375). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from two in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 10 of APC (PP3). Moreover, this variant has similar in silico predictions compared to another noncanonical splicing variant at that same nucleotide position (c.1312+3A>G) (ClinVar ID: 217924), which is classified as pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) (PS1). 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 HCCP VCEP: criteria PS1, PM2_Supporting, PP3, and PS4_Moderate applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 18, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1312+3A>C intronic pathogenic mutation results from an A to C substitution 3 nucleotides after coding exon 9 in the APC gene. This alteration has been detected in an individual diagnosed with >100 adenomatous polyps (Tsukanov AS et al. Russian J of Genet. 2017;53(3):369-375). Another alteration impacting the same donor site (c.1312+3A>G) has been detected in numerous familial adenomatous polyposis (FAP) families (Aretz S, et al. Hum. Mutat. 2004 Nov; 24(5):370-80; Lagarde A, et al. J. Med. Genet. 2010 Oct; 47(10):721-2; Nielsen M, et al. Clin. Genet. 2007 May; 71(5):427-33; Filipe B, et al. Clin. Genet. 2009 Sep; 76(3):242-55; Ambry internal data) and RNA analysis has shown that the c.1312+3A>G alteration leads to exon 9 skipping (Ambry internal data; Aretz S et al. Hum Mutat. 2004 Nov;24(5):370-80). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.97
PhyloP100		5.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.88		Position offset: -3

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

Other links and lift over

dbSNP: rs863225311; hg19: chr5-112155044; COSMIC: COSV57382696;