chr5-112707527-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_001407446.1(APC):​c.-191T>G 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)

Consequence

APC
NM_001407446.1 5_prime_UTR

Scores

2

Clinical Significance

Likely pathogenic criteria provided, single submitter P: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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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/exons MANE Protein UniProt
APCNM_001127511.3 linkuse as main transcriptc.-191T>G 5_prime_UTR_variant 1/14 NP_001120983.2
APCNM_001354895.2 linkuse as main transcriptc.-374T>G 5_prime_UTR_variant 1/16 NP_001341824.1
APCNM_001354897.2 linkuse as main transcriptc.-191T>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.-191T>G 5_prime_UTR_variant 1/142 ENSP00000423224
APCENST00000509732.6 linkuse as main transcriptc.-141T>G 5_prime_UTR_variant 1/164 ENSP00000426541 P1
APCENST00000505350.2 linkuse as main transcriptc.-191T>G 5_prime_UTR_variant, NMD_transcript_variant 1/163 ENSP00000481752

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
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 24, 2024The 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

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-112043224; API