rs1554071617

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The ENST00000257430.9(APC):​c.531+1_531+4delGTAA variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC ENST00000257430.9 splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012775433 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.9, offset of 0 (no position change), new splice context is: aatGTaact. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112775737-TGTAA-T is Pathogenic according to our data. Variant chr5-112775737-TGTAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 537529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112775737-TGTAA-T is described in Lovd as [Pathogenic].

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1

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

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;