chr5-112838677-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000038.6(APC):c.3083G>T(p.Ser1028Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1028N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.3083G>T | p.Ser1028Ile | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.3083G>T | p.Ser1028Ile | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461842Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727222
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:1Uncertain:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel | Feb 25, 2023 | The c.3083G>T variant in APC is a missense variant predicted to cause the substitution of serine by isoleucine at amino acid position 1028 (p.Ser1028Ile). This variant has been reported in 6 individuals resulting in a total phenotype score of 4.5 (PS4, Ambry, Invitae, Melbourne internal data). Another missense variant c.3084T>A (p.Ser1028Arg) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP (PM5_Supporting). Splicing prediction using SpliceAI and varSEAK revealed no expected effects on splicing due to any of these variants. Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4, PM2_Supporting, and PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2017 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with APC-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with isoleucine at codon 1028 of the APC protein (p.Ser1028Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. - |
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 19, 2020 | The p.S1028I variant (also known as c.3083G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 3083. The serine at codon 1028 is replaced by isoleucine, an amino acid with dissimilar properties. Another likely pathogenic variant at the same nucleotide position, p.S1028N (c.3083G>A), has segregated with disease in a family with attenuated familial adenomatous polyposis (AFAP) and colorectal cancer (Ambry internal data). In addition, internal structural analysis for the p.S1028N variant indicated that this lies on the protein interface important for β-Catenin binding (Ambry internal data). The p.S1028I amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at