rs778376399
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000038.6(APC):āc.7916A>Cā(p.Glu2639Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2639D) has been classified 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 -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.7916A>C | p.Glu2639Ala | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.7916A>C | p.Glu2639Ala | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250732Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135726
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461616Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727138
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2023 | The p.E2639A variant (also known as c.7916A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 7916. The glutamic acid at codon 2639 is replaced by alanine, an amino acid with dissimilar properties. 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 20, 2022 | This missense variant replaces glutamic acid with alanine at codon 2639 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282130 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. - |
Familial adenomatous polyposis 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 419575). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (rs778376399, gnomAD 0.002%). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 2639 of the APC protein (p.Glu2639Ala). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2015 | This variant is denoted APC c.7916A>C at the cDNA level, p.Glu2639Ala (E2639A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Glu2639Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Glu2639Ala occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located in the EB1 binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Glu2639Ala is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at