chr5-112707527-T-G

Variant names:

• chr5-112707527-T-G
• rs879253783
• ENST00000505350.2:n.-191T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The ENST00000505350.2(APC):​n.-191T>G 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. In-silico tool predicts a benign outcome for this variant. 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, single submitter P:1
• Conservation: PhyloP100: 2.92
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112707527-T-G is Pathogenic according to our data. Variant chr5-112707527-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1782658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NR_176365.1	n.30T>G		non_coding_transcript_exon_variant	Exon 1 of 13
APC	NR_176366.1	n.30T>G		non_coding_transcript_exon_variant	Exon 1 of 14
APC	NM_001407446.1	c.-191T>G		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.-191T>G		non_coding_transcript_exon_variant	Exon 1 of 16	3		ENSP00000481752.1
APC	ENST00000509732.6	c.-141T>G		5_prime_UTR_variant	Exon 1 of 16	4		ENSP00000426541.2
APC	ENST00000507379.6	c.-191T>G		5_prime_UTR_variant	Exon 1 of 14	2		ENSP00000423224.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 5

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 24, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-191T>G variant is located in the 5' untranslated region (5’ UTR) of the APC gene. This variant results from a T to G substitution 191 bases upstream from the first translated codon. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (Ambry internal data; Roberts AG et al. JPGN Reports, 2021 Nov;2(4):e123; Ishida A et al. Clin J Gastroenterol . 2024 Apr). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same position, (c.-191T>C), has been detected in multiple families with clinical diagnoses of GAPPS, shown to be a part of a highly conserved transcription factor binding site, and shown to have significantly decreased transcriptional activity in luciferase-based functional studies (Ambry internal data, Li J et al. Am J Hum Genet 2016 05;98(5):830-842). 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
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.91
PhyloP100		2.9
PromoterAI		-0.59	Under-expression

Splicing

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

Other links and lift over

dbSNP: rs879253783; hg19: chr5-112043224;