chr5-112775624-AAT-A

Variant names:

• chr5-112775624-AAT-A
• rs863225354
• NM_000038.6:c.423-3_423-2delTA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.423-3_423-2del p.(?) variant in APC is an intronic variant which deletes two nucleotides at position -2 and -3 in intron 4. This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 (PS4_Supporting; Ambry Genetics, GeneDX and Invitae internal data). In addition, this variant has also been reported in over 20 individuals with a polyposis phenotype not meeting phenotypic criteria. The results from 2 in silico splicing predictors (VarSEAK and MaxEntScan) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 4 of APC, but SpliceAI predicts no impact (PP3 not met). This variant is absent from gnomAD v2.1.1 non-cancer dataset (PM2_Supporting). In summary, this variant is a VUS for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_Supporting, PM2_Supporting (VCEP specifications version 1; date of approval 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA038361/MONDO:0021056/089

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: APC NM_000038.6 splice_acceptor, splice_region, intron
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U:3
• Conservation: PhyloP100: 4.78
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.423-3_423-2delTA		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 4 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.423-4_423-3delAT		splice_region_variant, intron_variant	Intron 4 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243264 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429602 Hom.: 0 AF XY: 0.00000140 AC XY: 1 AN XY: 712290

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32440

American (AMR) AF: 0.00 AC: 0 AN: 43540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.00 AC: 0 AN: 82588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5358

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088238

Other (OTH) AF: 0.00 AC: 0 AN: 59128

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2 Uncertain:1

Feb 01, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with clinical features of APC-related conditions (PMID: 20223039, 23159591, 33011440; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217982). 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 5, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 33011440; internal data). For these reasons, this variant has been classified as Pathogenic. -

Feb 18, 2023

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.423-3_423-2del p.(?) variant in APC is an intronic variant which deletes two nucleotides at position -2 and -3 in intron 4. This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 (PS4_Supporting; Ambry Genetics, GeneDX and Invitae internal data). In addition, this variant has also been reported in over 20 individuals with a polyposis phenotype not meeting phenotypic criteria. The results from 2 in silico splicing predictors (VarSEAK and MaxEntScan) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 4 of APC, but SpliceAI predicts no impact (PP3 not met). This variant is absent from gnomAD v2.1.1 non-cancer dataset (PM2_Supporting). In summary, this variant is a VUS for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_Supporting, PM2_Supporting (VCEP specifications version 1; date of approval 12/12/2022). -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes two basepairs, c.423-3_423-2del, in the intron 4 acceptor site of the APC gene. This variant is reported to cause abnormal splicing (ClinVar SCV001183798.3) and two similar variants c.423-5_423-3del (synonymous to c.423-4_423-2del) and c.423-3T>A have been reported to cause an estimated 80% to complete out-of-frame skipping of exon 5, respectively (PMID: 25676610, 33011440). This variant is highly similar to c.423-3T>A in terms of the variant acceptor site and its predicted splicing impact, and it may be reported as this alternate cDNA variant description by external laboratories and databases. The variant creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal adenoma (PMID: 33436027) and in individuals with clinical diagnosis of familial adenomatous polyposis, attenuated familial adenomatous polyposis or clinical features of APC-related conditions (ClinVar: SCV000552499.7, SCV001183798.3). Similar variants, c.423-3T>A and c.423-3delT have been reported in multiple individuals affected with familial adenomatous polyposis (PMID: 20223039, 30580288; External laboratory communication (ClinVar: SCV000186122.8, SCV000814096.5)) and c.423-3T>A has been reported to segregate with disease in multiple members of a family affected by polyposis or colorectal cancer (PMID: 30580288). This variant has been identified in 1/243264 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.423-3_423-2delTA intronic pathogenic mutation results from a deletion of two nucleotides at positions c.423-3 and c.423-2 and involves the canonical splice acceptor site before coding exon 4 of the APC gene. Although In silico splice site analysis for this alteration is inconclusive, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant has been observed in multiple individuals with a personal and/or family history that is consistent with APC-associated polyposis conditions (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1 Uncertain:1

Mar 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APC c.423-3_423-2del variant has not been reported in individuals with APC-related conditions in the published literature. However, similar overlapping intronic variants have been reported in individuals affected with familial adenomatous polyposis (PMID: 30580288 (2019)), and may impact splicing (PMIDs: 33436027 (2021), 33011440 (2020)). The frequency of this variant in the general population, 0.0000041 (1/243264 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on APC mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jun 30, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Also known as c.423-3T>A; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23159591, 20223039, 28051113, 28152038, 33436027, 30580288, 33011440) -

not specified Uncertain:1

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 5

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

Other links and lift over

dbSNP: rs863225354; hg19: chr5-112111321;