rs1168791940
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000038.6(APC):c.592G>A(p.Val198Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V198A) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.592G>A | p.Val198Ile | missense_variant | 6/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.592G>A | p.Val198Ile | missense_variant | 6/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461272Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726920
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 12, 2017 | The p.Val198Ile variant in APC has not been previously reported in individuals w ith APC-associated polyposis or in large population studies. Computational predi ction tools and conservation analysis suggest that the p.Val198Ile variant may n ot impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val198Ile vari ant is uncertain. - |
Familial adenomatous polyposis 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2021 | This sequence change replaces valine with isoleucine at codon 198 of the APC protein (p.Val198Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC 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: 505513). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2022 | The p.V198I variant (also known as c.592G>A), located in coding exon 5 of the APC gene, results from a G to A substitution at nucleotide position 592. The valine at codon 198 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in a study of 1,165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at