5-112840557-A-G
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000038.6(APC):āc.4963A>Gā(p.Thr1655Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000106 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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.4963A>G | p.Thr1655Ala | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+11585A>G | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250776Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135524
GnomAD4 exome AF: 0.000116 AC: 170AN: 1461842Hom.: 0 Cov.: 66 AF XY: 0.000117 AC XY: 85AN XY: 727222
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:4
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 threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1655 of the APC protein (p.Thr1655Ala). This variant is present in population databases (rs759441332, gnomAD 0.002%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 30267214). ClinVar contains an entry for this variant (Variation ID: 236610). 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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not provided Uncertain:4
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer and/or polyps, breast cancer, and glioma (Tung et al., 2015; Zhang et al., 2015; Rosenthal et al., 2018); This variant is associated with the following publications: (PMID: 25186627, 18199528, 30267214, 26580448) -
Variant summary: The APC c.4963A>G (p.Thr1655Ala) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant was found in 1/123124 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a Variant of Uncertain Significance (VUS), until additional information becomes available. -
The APC c.4963A>G (p.Thr1655Ala) variant has been reported in the published literature in individuals with colorectal cancer (PMID: 30267214 (2018)), breast cancer (PMID: 25186627 (2015)), and glioma (PMID: 26580448 (2015)). It has also been observed in a reportedly healthy individual (PMID: 18199528 (2008)). The frequency of this variant in the general population, 0.000044 (5/113144 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
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Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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This missense variant replaces threonine with alanine at codon 1655 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 been reported in individuals affected with glioma, breast, and colorectal cancer in the literature (PMID: 25186627, 26580448,30267214), and has also been reported in a healthy individual (PMID: 18199528). This variant has been identified in 6/250776 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. -
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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Classic or attenuated familial adenomatous polyposis Uncertain:1
This missense variant replaces threonine with alanine at codon 1655 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 been reported in individuals affected with glioma, breast, and colorectal cancer in the literature (PMID: 25186627, 26580448,30267214), and has also been reported in a healthy individual (PMID: 18199528). This variant has been identified in 6/250776 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. -
Desmoid disease, hereditary;C2713442:Familial adenomatous polyposis 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at