Variant 5-112707527-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001407446.1(APC):c.-191T>C variant causes a 5 prime UTR 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

APC
NM_001407446.1 5_prime_UTR

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 2.92

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-112707527-T-C is Pathogenic according to our data. Variant chr5-112707527-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 243005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.17). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
APC	NM_001407446.1 link	c.-191T>C	5_prime_UTR_variant	Exon 1 of 16	NP_001394375.1
APC	NM_001407447.1 link	c.-374T>C	5_prime_UTR_variant	Exon 1 of 17	NP_001394376.1
APC	NM_001407448.1 link	c.-141T>C	5_prime_UTR_variant	Exon 1 of 17	NP_001394377.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
APC	ENST00000509732 link	c.-141T>C	5_prime_UTR_variant	Exon 1 of 16	4	ENSP00000426541.2	D6RFL6
APC	ENST00000507379 link	c.-191T>C	5_prime_UTR_variant	Exon 1 of 14	2	ENSP00000423224.2	A0A2Q2SV78
APC	ENST00000505350.2 link	n.-191T>C	non_coding_transcript_exon_variant	Exon 1 of 16	3	ENSP00000481752.1	A0A087WYF3
APC	ENST00000505350.2 link	n.-191T>C	5_prime_UTR_variant	Exon 1 of 16	3	ENSP00000481752.1	A0A087WYF3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

328802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

170706

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Feb 05, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Describes a nucleotide substitution 191 base pairs upstream of the ATG translational start site of the APC promoter 1B region Published functional studies demonstrate a damaging effect: decreased YY1 binding and significantly reduced transcriptional activity compared to wild-type (Li 2016) Also defined as APC c.-30417T>C using an alternate reference sequence (NM_000038.5) This variant is associated with the following publications: (PMID: 32895333, 27087319, 27343414, 29968043) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APC: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Jan 10, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-191T>C pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the APC gene. This pathogenic mutation results from a T to C substitution 191 bases upstream from the first translated codon. This alteration has been described in five families with clinically-confirmed gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). In all five of these families, the mutation was detected in the germline of all available affected individuals, and it was not detected in available unaffected individuals, showing strong segregation with disease (Repak R et al. Gastrointest. Endosc. 2016 Oct;84:718-25; Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). The alteration impacts a highly-conserved nucleotide within the YY1 binding motif of APC promoter 1B, and authors demonstrated disrupted protein binding associated with c.-191T>C. Furthermore, luciferase assay results showed significantly reduced promoter activity for this variant compared to wild type (Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). This nucleotide position is highly conserved on limited sequence alignment. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Dec 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the 5' untranslated region of the APC gene. This variant is reported as c.-191T>C on an alternative transcript NM_001127511.3. A functional study has shown this variant results in significantly decreased transcriptional activity compared to wild type protein in colorectal cancer and gastric cancer cell lines (PMID: 27087319). This variant has been reported in individuals and families affected with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 2996804, 31409086). It has been shown that this variant segregates with GAPPS syndrome in numerous families (PMID: 2996804, 31409086). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Familial adenomatous polyposis 1

Pathogenic:1Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 02-21-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 27087319, 27343414). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-191T>C. ClinVar contains an entry for this variant (Variation ID: 243005). Studies have shown that this variant alters APC gene expression (PMID: 27087319). For these reasons, this variant has been classified as Pathogenic. -

Gastric adenocarcinoma and proximal polyposis of the stomach

Pathogenic:1

Feb 23, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.92

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over