10-87933181-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_000314.8(PTEN):​c.422A>G​(p.His141Arg) 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).

Frequency

Genomes: not found (cov: 32)

Consequence

PTEN
NM_000314.8 missense

Scores

9
7
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 8.88
Variant links:
Genes affected
PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a helix (size 12) in uniprot entity PTEN_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000314.8
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.1129 (above the threshold of 3.09). GenCC associations: The gene is linked to Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTENNM_000314.8 linkc.422A>G p.His141Arg missense_variant Exon 5 of 9 ENST00000371953.8 NP_000305.3
PTENNM_001304717.5 linkc.941A>G p.His314Arg missense_variant Exon 6 of 10 NP_001291646.4 P60484
PTENNM_001304718.2 linkc.-329A>G 5_prime_UTR_variant Exon 4 of 9 NP_001291647.1 P60484

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTENENST00000371953.8 linkc.422A>G p.His141Arg missense_variant Exon 5 of 9 1 NM_000314.8 ENSP00000361021.3 P60484-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:2
Jul 25, 2019
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PTEN c.422A>G (p.His141Arg) variant is a missense variant that has been reported in a cohort of 1012 Cowden syndrome patients meeting relaxed International Cowden Consortium criteria (Nizialiek et al. 2015) and in a heterozygous state in an individual with breast cancer (Chong et al. 2014). No additional clinical or family details were provided in either case. The p.His141Arg variant is absent from the Genome Aggregation Database in a region of good sequencing coverage. It is therefore presumed to be rare. This variant is located within the highly conserved phosphatase domain of the PTEN protein. Missense changes within this domain have been shown to eliminate or reduce phosphatase activity (Han et al. 2000). However, functional studies of the p.His141Arg variant have not been conducted. Missense variants in this domain have been identified in patients (Ali et al. 1999; Eng et al. 2003), but other missense changes affecting His141 have not been reported in the primary literature. Based on the collective evidence, the p.His141Arg variant is classified as a variant of uncertain significance for PTEN hamartoma tumor syndrome. -

Nov 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 141 of the PTEN protein (p.His141Arg). 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: 25669429). ClinVar contains an entry for this variant (Variation ID: 418438). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTEN protein function. This variant disrupts the p.His141 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29706350, 29785012; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

not provided Pathogenic:1
Dec 06, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified in multiple families with features consistent with PTEN Hamartoma Tumor syndrome referred for genetic testing at GeneDx and in published literature (PMID: 25669429); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14566704, 24830819, 29706350, 24475377, 32442409, 25669429) -

Hereditary cancer-predisposing syndrome Uncertain:1
Jul 15, 2013
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.21
D
MutationAssessor
Benign
1.9
L
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-7.5
D
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0040
D
Sift4G
Benign
0.072
T
Polyphen
1.0
D
Vest4
0.89
MutPred
0.57
Gain of MoRF binding (P = 0.0116);
MVP
0.94
MPC
1.8
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.97
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs863224666; hg19: chr10-89692938; API