10-87965294-T-G

Variant names:

• chr10-87965294-T-G
• rs1554826024
• NM_000314.8:c.1034T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000314.8(PTEN):​c.1034T>G​(p.Leu345Arg) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.64

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• 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, 0.938
• PP5: Variant 10-87965294-T-G is Pathogenic according to our data. Variant chr10-87965294-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 802613.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1034T>G	p.Leu345Arg	missense_variant	Exon 9 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1553T>G	p.Leu518Arg	missense_variant	Exon 10 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.443T>G	p.Leu148Arg	missense_variant	Exon 9 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1034T>G	p.Leu345Arg	missense_variant	Exon 9 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1 Uncertain:1

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 345 of the PTEN protein (p.Leu345Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 21659347; internal data). ClinVar contains an entry for this variant (Variation ID: 802613). 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) indicates that this missense variant is not expected to disrupt PTEN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 29785012). 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. -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.9	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.94	P
Vest4		0.93
MutPred		0.75		Gain of MoRF binding (P = 0.0084);
MVP		0.98
MPC		2.7
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.95
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1554826024; hg19: chr10-89725051;