rs727504420
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000038.6(APC):c.4255del(p.Ser1419AlafsTer54) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I1418I) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
APC
NM_000038.6 frameshift
NM_000038.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.570
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 12 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 345 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-112839847-TA-T is Pathogenic according to our data. Variant chr5-112839847-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177952.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.4255del | p.Ser1419AlafsTer54 | frameshift_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.4255del | p.Ser1419AlafsTer54 | frameshift_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial multiple polyposis syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2011 | The Ser1419fsx54 variant has not been previously reported in the literature or b een identified by our laboratory. However, an adjacent nucleotide variant, 4256d elG, resulting in a similar amino acid change, Ser1419fsX54, was identified in t umor tissue from an individual with colorectal carcinoma but not FAP (Lovig 2002 ; COSMIC). The Ser1419fsx54 variant is predicted to cause a frameshift, which al ters the protein's amino acid sequence beginning at codon 1419 and leads to a pr emature stop codon 54 amino acids downstream. From this DNA sequencing test, we cannot determine the effect this nucleotide change will have on the protein prod uced. It is possible that a truncated protein is generated. Alternatively, no pr otein would be produced from this allele if nonsense-mediated decay occurs, as p remature stop codons frequently result in degradation of the mRNA. Frameshift va riants in APC are commonly observed to be pathogenic, and loss of function of AP C is an established mechanism of disease in FAP (Human Mutation Gene Database, H GMD). Therefore, this variant is likely to be pathogenic. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at