chr5-112840165-T-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_000038.6(APC):āc.4571T>Gā(p.Ile1524Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,856 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1524V) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.4571T>G | p.Ile1524Arg | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.4571T>G | p.Ile1524Arg | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461856Hom.: 0 Cov.: 66 AF XY: 0.00000963 AC XY: 7AN XY: 727224
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1524 of the APC protein (p.Ile1524Arg). 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: 216165). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 23, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 02, 2023 | This missense variant replaces isoleucine with arginine at codon 1524 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. 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 | Mar 21, 2023 | The p.I1524R variant (also known as c.4571T>G), located in coding exon 15 of the APC gene, results from a T to G substitution at nucleotide position 4571. The isoleucine at codon 1524 is replaced by arginine, 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 09, 2024 | Variant summary: APC c.4571T>G (p.Ile1524Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4571T>G has been reported in the literature in individuals affected with Biliary tract cancer (Okawa_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis without evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36243179). ClinVar contains an entry for this variant (Variation ID: 216165). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
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 | Nov 02, 2023 | This missense variant replaces isoleucine with arginine at codon 1524 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at