5-112842985-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000038.6(APC):āc.7391C>Gā(p.Ser2464Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,966 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2464Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.7391C>G | p.Ser2464Cys | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.7391C>G | p.Ser2464Cys | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461752Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727176
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74370
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2464 of the APC protein (p.Ser2464Cys). This variant is not present in population databases (gnomAD no frequency). 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: 569210). 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
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 20, 2023 | This missense variant replaces serine with cysteine at codon 2464 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 not been identified 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 24, 2024 | The p.S2464C variant (also known as c.7391C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 7391. The serine at codon 2464 is replaced by cysteine, an amino acid with dissimilar 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 10, 2023 | To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000013 (2/152214 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 30, 2023 | - - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at