rs587780598
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000038.6(APC):c.5177A>G(p.Glu1726Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,872 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 Uncertain significance (★★).
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.5177A>G | p.Glu1726Gly | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+11799A>G | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250424Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135378
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461654Hom.: 0 Cov.: 64 AF XY: 0.00000138 AC XY: 1AN XY: 727126
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:3
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1726 of the APC protein (p.Glu1726Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 135707). 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. -
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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. -
Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces glutamic acid with glycine at codon 1726 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/245182 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
The p.E1726G variant (also known as c.5177A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 5177. The glutamic acid at codon 1726 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly 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. -
Classic or attenuated familial adenomatous polyposis Uncertain:1
This missense variant replaces glutamic acid with glycine at codon 1726 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/245182 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Malignant tumor of breast Uncertain:1
The APC p.Glu1726Gly variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (rs587780598) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and Counsyl). The variant was identified in control databases in 2 of 281,834 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 2 of 19,946 chromosomes (freq: 0.0001); it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, European, Other or South Asian populations. The p.Glu1726 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Gly variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at