rs786202753
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_000314.8(PTEN):āc.488A>Gā(p.Lys163Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,064 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K163Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.488A>G | p.Lys163Arg | missense_variant | 5/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.1007A>G | p.Lys336Arg | missense_variant | 6/10 | ||
PTEN | NM_001304718.2 | c.-263A>G | 5_prime_UTR_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.488A>G | p.Lys163Arg | missense_variant | 5/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1456064Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2AN XY: 724748
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 26, 2021 | This sequence change replaces lysine with arginine at codon 163 of the PTEN protein (p.Lys163Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 186180). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 26279303). 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 | All of Us Research Program, National Institutes of Health | Mar 28, 2023 | This missense variant replaces lysine with arginine at codon 163 of the PTEN 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies showed that this variant may abolish the induction of PTEN acetylation and membrane translocation by TSA (trichostatin A, histone deacetylase (HDAC) inhibitor), and it failed to facilitate the inhibition of cell proliferation, migration and invasion, as well as xenograft tumour growth induced by TSA (PMID: 26279303). This variant has not been reported in individuals affected with hereditary cancer 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. - |
Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 22, 2022 | The p.K163R variant (also known as c.488A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 488. The lysine at codon 163 is replaced by arginine, an amino acid with highly similar properties. Studies from one research group have shown that PTEN is activated by acetylation at the K163 residue, and the K163R variant abolished acetylation and membrane translocation of PTEN; however, the clinical implications of this alteration are unknown (Meng Z et al. Oncogene. 2016 05;35:2333-44; Zhang G et al. Oncol. Rep. 2017 Nov;38:2657-2666). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally wildtype-like (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This variant demonstrated wildtype-like intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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