rs886039507

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-112819349-G-A
• chr5-112819349-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3_Moderate PM2_Supporting PS4 PM6_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.1312+5G>A variant in APC is an intronic variant which is located at the 5th nucleotide in intron 10. This variant has been reported in 16 probands meeting phenotypic criteria, resulting in a total phenotype score of 11.5 points (internal data Labcorp Genetics [formerly Invitae], Ambry Genetics, Peter MacCallum Cancer Centre, Victoria, Australia, PMID:15459959 and 23159591) (PS4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). RNA studies have demonstrated that this variant causes exon 10 skipping (PMID:22987206, 15459959, 15833136, Ambry internal data) (PS3_Moderate). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with FAP, resulting in a total de novo score of 0.5 (PMID:15833136) (PM6_Supporting). 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, PM2_Supporting, PM6_Supporting (VCEP specifications version 2.1.0; date of approval: 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16611621/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:7
• 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 8 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.
• PM6: 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>A		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>A		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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Nov 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial adenomatous polyposis (PMID: 15459959, 20223039, 22987206). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411416). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10 (also referred to as exon 9) and introduces a premature termination codon (PMID: 15459959, 22987206). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

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.1312+5G>A variant in APC is an intronic variant which is located at the 5th nucleotide in intron 10. This variant has been reported in 16 probands meeting phenotypic criteria, resulting in a total phenotype score of 11.5 points (internal data Labcorp Genetics [formerly Invitae], Ambry Genetics, Peter MacCallum Cancer Centre, Victoria, Australia, PMID: 15459959 and 23159591) (PS4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). RNA studies have demonstrated that this variant causes exon 10 skipping (PMID: 22987206, 15459959, 15833136, Ambry internal data) (PS3_Moderate). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with FAP, resulting in a total de novo score of 0.5 (PMID: 15833136) (PM6_Supporting). 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, PM2_Supporting, PM6_Supporting (VCEP specifications version 2.1.0; date of approval: 11/24/2023). -

Sep 16, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 14, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the +5 position of intron 10 of the APC gene. RNA studies show that this variants resulted in exon 10 skipping (PMID: 8125478, 15459959, 15833136, 19196998, 22987206). This variant has been reported in individuals affected with familial adenomatous polyposis or colonic polyposis (PMID: 8125478, 15459959, 15833136, 22987206, 29029407, 29406563). It has been shown that this variant segregates with disease (PMID: 8125478). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Dec 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1312+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 9 in the APC gene. This mutation has been detected in individuals with clinical diagnoses of familial adenomatous polyposis (FAP) and attenuated FAP (Ambry internal data; Aretz et al. Hum Mutat. 2004 Nov;24(5):370-80; Mihalatos M et al. BMC Cancer 2005 Apr;5:40; Schwarzova et al. Fam Cancer. 2013 Mar;12(1):35-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). RNA analysis reveals that this mutation leads to substantially increased exon 9 skipping relative to control RNA samples (Ambry internal data; Aretz et al. Hum Mutat. 2004 Nov;24(5):370-80; Mihalatos M et al. BMC Cancer 2005 Apr;5:40; Schwarzova et al. Fam Cancer. 2013 Mar;12(1):35-42). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial multiple polyposis syndrome Pathogenic:1

Jul 10, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APC c.1312+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. Several publications report experimental evidence that this variant affects mRNA splicing, resulting in skipping of exon 9 and truncation of the protein (Aretz_2004, Mihalatos_2005, Schwarzova_2013). The variant was absent in 250464 control chromosomes. c.1312+5G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis(FAP) or Attenuated Familial Adenomatous Polyposis(AFAP) (Aretz_2004, Mihalatos_2005, Schwarzova_2013, Yanus_2018). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments of pathogenic for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Nov 19, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A splicing study showed that this variant produced a shift of frame, and is therefore predicted to result in the loss of a functional protein. Not found in the gnomAD dataset, and the data is high quality (0/34534 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to negatively affect a known splice site. Nucleotide conservation is uninformative. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.98
PhyloP100		9.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.52		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; COSMIC: COSV57358318;