5-112843402-A-G
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000038.6(APC):c.7808A>G(p.Glu2603Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,204 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.7808A>G | p.Glu2603Gly | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.229-13247A>G | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250266Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135284
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460978Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 726800
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74380
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:3
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This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2603 of the APC protein (p.Glu2603Gly). This variant is present in population databases (rs587779807, gnomAD 0.0009%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127321). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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. -
not specified Uncertain:1
Variant summary: APC c.7808A>G (p.Glu2603Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250266 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7808A>G has been reported in the literature in at-least one individual undergoing multigene hereditary cancer panel g for Lynch syndrome testing (example: Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127321). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach Uncertain:1
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not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual undergoing multi-gene cancer panel testing due to a personal history of a Lynch syndrome-related cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 18199528, 25980754) -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.E2603G variant (also known as c.7808A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 7808. The glutamic acid at codon 2603 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at