5-112707526-AT-TAGCAAGGG

Variant names:

• chr5-112707526-AT-TAGCAAGGG
• rs1580995904
• ENST00000505350.2:n.-192_-191delATinsTAGCAAGGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000505350.2(APC):​n.-192_-191delATinsTAGCAAGGG variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APC ENST00000505350.2 non_coding_transcript_exon
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.40
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112707526-AT-TAGCAAGGG is Pathogenic according to our data. Variant chr5-112707526-AT-TAGCAAGGG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 652807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NR_176365.1	n.29_30delATinsTAGCAAGGG		non_coding_transcript_exon_variant	Exon 1 of 13
APC	NR_176366.1	n.29_30delATinsTAGCAAGGG		non_coding_transcript_exon_variant	Exon 1 of 14
APC	NM_001407446.1	c.-192_-191delATinsTAGCAAGGG		5_prime_UTR_variant	Exon 1 of 16		NP_001394375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000505350.2	n.-192_-191delATinsTAGCAAGGG		non_coding_transcript_exon_variant	Exon 1 of 16	3		ENSP00000481752.1
APC	ENST00000509732.6	c.-142_-141delATinsTAGCAAGGG		5_prime_UTR_variant	Exon 1 of 16	4		ENSP00000426541.2
APC	ENST00000507379.6	c.-192_-191delATinsTAGCAAGGG		5_prime_UTR_variant	Exon 1 of 14	2		ENSP00000423224.2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1

Nov 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in an individual with clinical features consistent with familial adenomatous polyposis (Invitae). While experimental studies and prediction algorithms are not available for this variant, it disrupts a region of the APC promoter that has been proposed to include the DNA binding site for the YY1 transcription factor. Other variants that affect this region of the APC promoter (c.-30416G>A, c.-30417T>C, c.-30418A>G, and c.-30418A>T) have been shown to disrupt YY1 binding to the APC promoter and result in reduced APC expression (PMID: 20685668, 21813476, 27087319). Other variants that disrupt the DNA sequence in this region of the APC promoter have been observed in affected individuals (PMID: 20685668, 21813476, 27087319, 27343414, Invitae), suggesting that integrity of this region is clinically significant. As a result, variants that disrupt this region of the APC promoter are likely to be causative of disease. 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 21, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-192_-191delATinsTAGCAAGGG variant, located in in the 5' untranslated region (5’UTR) of the APC gene, results from the deletion of two nucleotides and the insertion of nine nucleotides at nucleotide positions -192 to -191 upstream of the first translated codon. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (Ambry internal data). Other alterations affecting these nucleotides (c.-192A>G, c.-191T>G, c.-191T>C) have been identified in GAPPS probands (Ambry internal data; Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42; Roberts AG et al. JPGN Reports, 2021 Nov;2(4):e123). This region has been identified as a highly conserved transcription factor binding site for the APC 1B promoter region and point mutations have been shown to disrupt transcriptional activity (Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4

Splicing

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

Other links and lift over

dbSNP: rs1580995904; hg19: chr5-112043223;