10-87952137-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000314.8(PTEN):c.512A>G(p.Gln171Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q171E) has been classified as Pathogenic.
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.512A>G | p.Gln171Arg | missense_variant | Exon 6 of 9 | ENST00000371953.8 | NP_000305.3 | |
PTEN | NM_001304717.5 | c.1031A>G | p.Gln344Arg | missense_variant | Exon 7 of 10 | NP_001291646.4 | ||
PTEN | NM_001304718.2 | c.-80A>G | 5_prime_UTR_variant | Exon 6 of 9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Classification criteria: PM2_supporting, PP3, PP2, PS3_moderate, PS2 -
Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
The p.Q171R variant (also known as c.512A>G), located in coding exon 6 of the PTEN gene, results from an A to G substitution at nucleotide position 512. The glutamine at codon 171 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a patient meeting clinical criteria for Cowden syndrome (Pal A et al. N Engl J Med, 2012 Sep;367:1002-11). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). In addition, this variant demonstrated low intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not specified Uncertain:1
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PTEN hamartoma tumor syndrome Uncertain:1
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. Experimental studies have shown that this missense change affects PTEN function (PMID: 34943931). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 171 of the PTEN protein (p.Gln171Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN-related conditions (PMID: 22970944, 35227301). ClinVar contains an entry for this variant (Variation ID: 189412). 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 expected to disrupt PTEN protein function. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at