rs753630034
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2
The NM_000314.8(PTEN):c.425G>A(p.Arg142Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R142W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.425G>A | p.Arg142Gln | missense_variant | 5/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.944G>A | p.Arg315Gln | missense_variant | 6/10 | ||
PTEN | NM_001304718.2 | c.-326G>A | 5_prime_UTR_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.425G>A | p.Arg142Gln | missense_variant | 5/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152008Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251364Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135866
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461688Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727148
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152008Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74248
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 142 of the PTEN protein (p.Arg142Gln). This variant is present in population databases (rs753630034, gnomAD 0.0009%). 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: 237646). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 95%. This variant disrupts the p.Arg142 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 23335809, 25669429; Invitae), which suggests that this may be a clinically significant amino acid residue. 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 | Nov 02, 2023 | This missense variant replaces arginine with glutamine at codon 142 of the PTEN protein. A massively parallel functional study done in a humanoid yeast model demonstrated this variant had no impact on lipid phosphatase activity (PMID: 29706350). This variant has not been reported in individuals affected with PTEN-related disorders in the literature. This variant has been identified in 1/251364 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. - |
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24475377) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2022 | The p.R142Q variant (also known as c.425G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 425. The arginine at codon 142 is replaced by glutamine, an amino acid with highly similar properties. In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally neutral (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This alteration has been reported as a somatic alteration in a variety of tumors (Hühns M et al. Oncol. Rep. 2014 May;31(5):2236-44; Sozopoulos E et al. Endocr. Pathol. 2010 Jun;21(2):90-100; Kuehn F et al. Sci Rep 2016;6:24671; Stjernström A et al. Cancer Med 2014 Apr;3(2):337-48). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 19, 2023 | This missense variant replaces arginine with glutamine at codon 142 of the PTEN protein. A massively parallel functional study done in a humanoid yeast model demonstrated this variant had no impact on lipid phosphatase activity (PMID: 29706350). This variant has not been reported in individuals affected with PTEN-related disorders in the literature. This variant has been identified in 1/251364 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at