5-112775742-G-C

Variant names:

• chr5-112775742-G-C
• rs587779798
• NM_000038.6:c.531+5G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PS4_Supporting PM2_Supporting PS3

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.531+5G>C variant in APC is an intronic variant which is located at the 5th nucleotide in intron 5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 2 families meeting phenotypic criteria, resulting in a total phenotype score of 1 point (PMID:19196998, 20223039, 12010888; the first two references refer to the same German family) (PS4_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). RNA studies have demonstrated that this variant causes exon 5 deletion (c.531+5G>C; r.423_531del; p.Arg144Serfs*8; PMID:19196998) (PS3). 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, PM2_Supporting and PP3 (VCEP specifications version 2.1.0; date of approval: 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10602909/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, intron
• Scores: Splicing: ADA: 0.9971
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 6.98
• 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 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.531+5G>C		splice_region_variant, intron_variant	Intron 5 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.531+5G>C		splice_region_variant, intron_variant	Intron 5 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

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.531+5G>C variant in APC is an intronic variant which is located at the 5th nucleotide in intron 5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 2 families meeting phenotypic criteria, resulting in a total phenotype score of 1 point (PMID: 19196998, 20223039, 12010888; the first two references refer to the same German family) (PS4_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). RNA studies have demonstrated that this variant causes exon 5 deletion (c.531+5G>C; r.423_531del; p.Arg144Serfs*8; PMID: 19196998) (PS3). 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, PM2_Supporting and PP3 (VCEP specifications version 2.1.0; date of approval: 11/24/2023). -

Jul 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 5 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein, but it affects a nucleotide within the consensus splice site of the intron. This variant has been observed in several individuals and families affected with familial adenomatous polyposis (PMID: 12010888, 19196998). Intron 5 is also known as intron 4 in the literature due to alternative exon numbering. ClinVar contains an entry for this variant (Variation ID: 279681). For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies in patient-derived leukocytes using RT-PCR of mRNA followed by cDNA sequencing showed that this variant results in the out-of-frame skipping of exon 5 (PMID: 19196998, 12010888). -

Apr 27, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 12010888]. -

not provided Pathogenic:1

May 13, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted APC c.531+5 G>C or IVS5+5 G>C and consists of a G>C nucleotide substitution at the +5 position of intron 5 of the APC gene. This variant has been observed in at least two individuals presenting with a phenotype suggestive of Attenuated Familial Adenomatous Polyposis (Moisio 2002, Kaufmann 2009). Importantly, Kaufmann et al. (2009) found via mRNA analysis that APC c.531+5 G>C results in the heterozygous deletion of exon 5 (published as exon 4 due to the use of alternate nomenclature). APC c.531+5 G>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations and the guanine (G) nucleotide that is altered is well conserved across species. Based on the current evidence, we consider APC c.531+5 G>C to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 06, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.531+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 4 in the APC gene. This alteration has been previously observed in families with both classic familial adenomatous polyposis (FAP) and attenuated FAP (Moisio AL et al. Gut 2002 Jun;50(6):845-50; Friedl W et al. Hered. Cancer Clin. Pract. 2005 Sep;3(3):95-114; Kaufmann A et al. J. Mol. Diagn. 2009 Mar;11(2):131-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Kaufmann A et al. J. Mol. Diagn. 2009 Mar;11(2):131-9; Ambry internal data). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.98
PhyloP100		7.0
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -5

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

Other links and lift over

dbSNP: rs587779798; hg19: chr5-112111439;