5-112841576-C-G
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_000038.6(APC):c.5982C>G(p.Asp1994Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1994V) has been classified as Likely benign.
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.5982C>G | p.Asp1994Glu | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+12604C>G | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250176Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135498
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461604Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8AN XY: 727112
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74340
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2
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This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1994 of the APC protein (p.Asp1994Glu). This variant is present in population databases (rs372852823, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 220442). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Hereditary cancer-predisposing syndrome Uncertain:2
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The p.D1994E variant (also known as c.5982C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 5982. The aspartic acid at codon 1994 is replaced by glutamic acid, an amino acid with highly similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum. Genet., 2018 Oct;137:795-806). Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). This amino acid position is not 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. -
not provided Uncertain:1
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18199528, 30267214) -
Classic or attenuated familial adenomatous polyposis Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at