10-87933166-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_001304718.2(PTEN):​c.-344G>T variant causes a 5 prime UTR premature start codon gain 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PTEN
NM_001304718.2 5_prime_UTR_premature_start_codon_gain

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.53
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 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 10-87933166-G-T is Pathogenic according to our data. Variant chr10-87933166-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1737618.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTENNM_000314.8 linkc.407G>T p.Cys136Phe missense_variant Exon 5 of 9 ENST00000371953.8 NP_000305.3
PTENNM_001304718.2 linkc.-344G>T 5_prime_UTR_premature_start_codon_gain_variant Exon 4 of 9 NP_001291647.1 P60484
PTENNM_001304717.5 linkc.926G>T p.Cys309Phe missense_variant Exon 6 of 10 NP_001291646.4 P60484
PTENNM_001304718.2 linkc.-344G>T 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.407G>T p.Cys136Phe 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

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 20, 2021The p.C136F pathogenic mutation (also known as c.407G>T), located in coding exon 5 of the PTEN gene, results from a G to T substitution at nucleotide position 407. The cysteine at codon 136 is replaced by phenylalanine, an amino acid with highly dissimilar properties. In a functional study, this variant demonstrated deficient phosphatase activity (Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955). Two other alterations at the same codon, p.C136R (c.406T>C) and p.C136Y (c.407G>A), have been detected in individuals with features consistent with PTEN Hamartoma Tumor Syndrome (PHTS) (Kubo Y et al. Br. J. Dermatol. 2000 Jun;142(6):1100-5; Galatola M et al. BMC Med. Genet., 2012 Apr;13:28; Matsumoto K et al. Diagn. Pathol. 2015 Sep;10:172; Ambry internal data). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.61
CADD
Pathogenic
34
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.96
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-9.0
D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.87
MutPred
0.85
Gain of MoRF binding (P = 0.0648);
MVP
0.98
MPC
2.7
ClinPred
1.0
D
GERP RS
5.2
Varity_R
1.0
gMVP
0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-89692923; COSMIC: COSV64294671; API