rs587781451
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.935dup(p.Glu313GlyfsTer14) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V312V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000038.6 frameshift, splice_region
Scores
Clinical Significance
Conservation
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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.935dup | p.Glu313GlyfsTer14 | frameshift_variant, splice_region_variant | 10/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.935dup | p.Glu313GlyfsTer14 | frameshift_variant, splice_region_variant | 10/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 28, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 26, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 141040). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu313Glyfs*14) 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). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2015 | This duplication of one nucleotide in APC is denoted c.935dupT at the cDNA level and p.Glu313GlyfsX14(E313GfsX14) at the protein level. The normal sequence, with the base that is duplicated in braces, is cagG[T]GGAA with lower case letters being intronic and upper case letters being exonic. The duplication causes a frameshift, which changes a Glutamic Acid to a Glycine at codon 313 in exon 10, and creates a premature stop codon at position 14 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic. - |
Likely pathogenic, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant is located in the APC protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 05, 2023 | The c.935dupT pathogenic mutation, located in coding exon 9 of the APC gene, results from a duplication of T at nucleotide position 935, causing a translational frameshift with a predicted alternate stop codon (p.E313Gfs*14). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). 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. - |
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 03, 2021 | This frameshift variant is predicted to cause the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations. - |
Classic or attenuated familial adenomatous polyposis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 09, 2023 | The c.935dup (p.Glu313Glyfs*14) variant in the APC gene is located on the exon 10 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Glu313Glyfs*14), resulting in an absent or disrupted protein product. Loss-of-function variants of APC are known to be pathogenic and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with familial adenomatous polyposis/colorectal cancer (PMID: 23159591, 31591141, 33769591). Frameshift variants at codon 313 have been reported in 4 individuals with familial adenomatous polyposis/colorectal cancer (PMID: 9916927, 11960572, 28135145). The variant is reported in ClinVar (ID: 141040). The variant is absent in the general population database (gnomAD). Therefore, the c.935dup (p.Glu313Glyfs*14) variant of APC has been classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at