rs1554085659

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000038.6(APC):​c.4241delT​(p.Val1414fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

APC
NM_000038.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.84
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 Pathogenic. Variant got 11 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 53 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-112839834-GT-G is Pathogenic according to our data. Variant chr5-112839834-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 433659.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-112839834-GT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APCNM_000038.6 linkuse as main transcriptc.4241delT p.Val1414fs frameshift_variant 16/16 ENST00000257430.9 NP_000029.2 P25054-1Q4LE70

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkuse as main transcriptc.4241delT p.Val1414fs frameshift_variant 16/165 NM_000038.6 ENSP00000257430.4 P25054-1
ENSG00000258864ENST00000520401.1 linkuse as main transcriptn.228+10863delT intron_variant 3 ENSP00000454861.1 H3BNH8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Carcinoma of colon Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The p.Val1414GlufsX5 deletion is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1414 and leads to a premature stop codon 5 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. In addition, the p.Val1414GlufsX5 deletion has been previously reported in the literature in at least one individual in a "sporadic" tumour from an invasive carcinoma, supporting a pathogenic role for this deletion (Miyaki 1994). It should be noted that this sequence alteration is of the type that is expected to cause the disorder. In summary, based on the above information, the p.Val1414GlufsX5 deletion is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs1554085659; hg19: chr5-112175531; COSMIC: COSV57325736; COSMIC: COSV57325736; API