5-112819349-G-C

Variant names:

• chr5-112819349-G-C
• rs886039507
• NM_000038.6:c.1312+5G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PS4_Moderate PS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.1312+5G>C variant in APC is an intronic variant which is located at the 5th nucleotide in intron 10. This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 2.5 points (PS4_Moderate, Ambry Genetics, GeneDx, Invitae internal data). 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 non-canonical splicing variant at that same nucleotide position (c.1312+5G>A) which is classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) (PS1_Moderate). 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 HCCP VCEP: PP3, PS1_Moderate, PS4_Moderate, PM2_Supporting (VCEP specifications version 2.1.0; date of approval: 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10588378/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.60
• Publications: 2 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.

• 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+5G>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+5G>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:4

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Sep 25, 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. This variant disrupts the c.1312+5G nucleotide in the APC gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15459959, 20223039, 22987206). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: 265372). This variant has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 23159591). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein. It affects a nucleotide within the consensus splice site.

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+5G>C variant in APC is an intronic variant which is located at the 5th nucleotide in intron 10. This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 2.5 points (PS4_Moderate, Ambry Genetics, GeneDx, Invitae internal data). 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 non-canonical splicing variant at that same nucleotide position (c.1312+5G>A) which is classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) (PS1_Moderate). 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 HCCP VCEP: PP3, PS1_Moderate, PS4_Moderate, PM2_Supporting (VCEP specifications version 2.1.0; date of approval: 11/24/2023).

not provided Pathogenic:1

May 12, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted APC c.1312+5G>C or IVS10+5G>C and consists of a G>C nucleotide substitution at the +5 position of intron 10 of the APC gene. Multiple in silico models predict this variant to destroy the nearby natural donor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Importantly, two other variants impacting the same nucleotide, APC c.1312+5G>A and c.1312+5G>T, have both been shown in RNA based assays to result in skipping of exon 10, also published as exon 9, resulting in a frameshift and a subsequent premature stop codon (Mihalatos 2005, Varesco 1994). This variant, APC c.1312+5G>C, has been observed in one individual undergoing APC testing at a clinical laboratory (Kerr 2013). APC c.1312+5G>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. Based on the currently available information, we consider APC c.1312+5G>C to be a likely pathogenic variant.

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 21, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1312+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 9 in the APC gene. This alteration has been reported in multiple individuals with personal and/or family history consistent with Familial Adenomatous Polyposis (FAP) and /or Attenuated FAP (AFAP) (Ambry internal data, Kerr SE. J Mol Diagn . 2013 Jan;15(1):31-43). A close match alteration, designated as IVS9+5G>A, has been reported in a patient with multiple small polyps in the right colon and was reported as confirmed de novo via familial testing in this patient (Mihalatos M et al. BMC Cancer, 2005 Apr;5:40). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Further, multiple other pathogenic alterations have been reported at this splice junction, including c.1312+3A>G and c.1312+5G>A. 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	-0.29
CADD	Benign	23
DANN	Uncertain	0.98
PhyloP100		9.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.45		Position offset: -5

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

Other links and lift over

dbSNP: rs886039507; hg19: chr5-112155046;