5-112707527-T-C

Position:

• chr5-112707527-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 2.92

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 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	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_001127511.3	c.-191T>C		5_prime_UTR_variant	1/14
APC	NM_001354895.2	c.-374T>C		5_prime_UTR_variant	1/16
APC	NM_001354897.2	c.-191T>C		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000507379.6	c.-191T>C		5_prime_UTR_variant	1/14	2
APC	ENST00000509732.6	c.-141T>C		5_prime_UTR_variant	1/16	4		P1
APC	ENST00000505350.2	c.-191T>C		5_prime_UTR_variant, NMD_transcript_variant	1/16	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 328802 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 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.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	APC: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2021	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 06, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2023	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. -

Familial adenomatous polyposis 1 Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879253783; hg19: chr5-112043224;