chr5-112775681-T-TA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.476dup(p.Tyr159Ter) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y159Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000038.6 stop_gained, frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.476dup | p.Tyr159Ter | stop_gained, frameshift_variant | 5/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.476dup | p.Tyr159Ter | stop_gained, frameshift_variant | 5/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1456436Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 724268
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 16, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 236607). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 8956059, 20223039, 20685668). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr159*) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 18, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 01, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28944238, 20223039, 15951963, 20685668, 23159591, 27623068, 8956059) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 18, 2020 | PVS1, PM2, PP4 - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 20, 2023 | The c.476dupA pathogenic mutation, located in coding exon 4 of the APC gene, results from a duplication of A at nucleotide position 476, causing a translational frameshift with a predicted alternate stop codon (p.Y159*). This variant was identified in 1/863 colonic polyposis patients from a French cohort (Lagarde A et al. J Med Genet, 2010 Oct;47:721-2). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at