rs1554071617

Variant names:

• chr5-112775737-TGTAA-T
• rs1554071617
• NM_000038.6:c.531+5_531+8delGTAA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PS3_Moderate PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.531+5_531+8del variant is located in intron 5 of the APC gene. RT-PCR demonstrated that this variant impacts splicing by skipping of exon 5 resulting in a premature stop codon (PS3_Moderate, PMID:15459959). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). This variant has been reported in 5 probands meeting phenotypic criteria, resulting in a total phenotype score of 3.5 (PS4_Moderate; internal data Labcorp Genetics [formerly Invitae] and Institute of Human Genetics, Bonn, Germany, PMID:15459959 and 20223039). The results from two in silico splicing predictors (SpliceAI and VarSeak) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). 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, PM2_Supporting, PP3, and PS4_Moderate (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA658760464/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC ENST00000257430.9 splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.19

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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+5_531+8delGTAA		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+1_531+4delGTAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 5 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

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+5_531+8del variant is located in intron 5 of the APC gene. RT-PCR demonstrated that this variant impacts splicing by skipping of exon 5 resulting in a premature stop codon (PS3_Moderate, PMID: 15459959). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). This variant has been reported in 5 probands meeting phenotypic criteria, resulting in a total phenotype score of 3.5 (PS4_Moderate; internal data Labcorp Genetics [formerly Invitae] and Institute of Human Genetics, Bonn, Germany, PMID: 15459959 and 20223039). The results from two in silico splicing predictors (SpliceAI and VarSeak) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). 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, PM2_Supporting, PP3, and PS4_Moderate (VCEP specifications version v2.1.0; date of approval 11/24/2023). -

Jan 01, 2018

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. A different variant that affects the +5 position of intron 5 of APC gene in the same way as this variant (c.531+5G>C) has been determined to be pathogenic (PMID: 19196998, 12010888). This suggests that the +5 position in this intron is important for normal RNA splicing, and that other variants that affect this position may also be pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change can result in skipping of exon 4 of the APC mRNA (PMID: 15459959). This variant has been reported in an individual affected with familial adenomatous polyposis (PMID: 15459959). 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. -

Inherited polyposis and early onset colorectal cancer - germline testing Pathogenic:1

Sep 19, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1_Moderate,PS3,PS4_Supporting,PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554071617; hg19: chr5-112111434;