5-112707526-A-G

Variant summary

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

The NM_001407446.1(APC):​c.-192A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 479,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000031 ( 0 hom. )

Consequence

APC
NM_001407446.1 5_prime_UTR

Scores

2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.40
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]

Genome browser will be placed here

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 5-112707526-A-G is Pathogenic according to our data. Variant chr5-112707526-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 243006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.18). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APCNM_001127511.3 linkuse as main transcriptc.-192A>G 5_prime_UTR_variant 1/14 NP_001120983.2
APCNM_001354895.2 linkuse as main transcriptc.-375A>G 5_prime_UTR_variant 1/16 NP_001341824.1
APCNM_001354897.2 linkuse as main transcriptc.-192A>G 5_prime_UTR_variant 1/15 NP_001341826.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APCENST00000507379.6 linkuse as main transcriptc.-192A>G 5_prime_UTR_variant 1/142 ENSP00000423224
APCENST00000509732.6 linkuse as main transcriptc.-142A>G 5_prime_UTR_variant 1/164 ENSP00000426541 P1
APCENST00000505350.2 linkuse as main transcriptc.-192A>G 5_prime_UTR_variant, NMD_transcript_variant 1/163 ENSP00000481752

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152236
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000306
AC:
1
AN:
327140
Hom.:
0
Cov.:
5
AF XY:
0.00000588
AC XY:
1
AN XY:
169940
show subpopulations
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:
0.0000557
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152236
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 24, 2023This 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 present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individuals with clinical features of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 27087319; Invitae). This variant is also known as c.-192A>G. ClinVar contains an entry for this variant (Variation ID: 243006). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects APC function (PMID: 27087319). 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. -
Gastric adenocarcinoma and proximal polyposis of the stomach Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 12, 2021- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJan 25, 2021Describes a nucleotide substitution 192 base pairs upstream of the ATG translational start site of the APC promoter 1B region; Published functional studies demonstrate a damaging effect: disrupted binding to the YY1 transcription factor and impaired activity of the APC promoter 1B in gastric and colorectal cancer cell lines, allelic imbalance in patient cells suggesting decreased allele-specific expression in vivo (Li 2016); Identified in two siblings with fundic gland polyposis, one of whom also had gastric cancer (Li 2016); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27087319, 29141268, 21813476, 30584346, 31409086) -
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 29, 2023The c.-192A>G variant is located in the 5' untranslated region (5’ UTR) of the APC gene. This variant results from an A to G substitution 192 bases upstream from the first translated codon. In one study, this variant was identified in 2 siblings affected with fundic gland polyposis (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.-192A>G. Furthermore, luciferase assay results showed significantly reduced promoter activity for this variant compared to wild type. 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
-0.18
CADD
Benign
21
DANN
Benign
0.90

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.

Other links and lift over

dbSNP: rs879253784; hg19: chr5-112043223; API