10-87933126-C-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):c.367C>G(p.His123Asp) 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H123R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.51

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87933127-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7816.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 10-87933126-C-G is Pathogenic according to our data. Variant chr10-87933126-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 428277.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-87933126-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.367C>G	p.His123Asp	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.886C>G	p.His296Asp	missense_variant	6/10
PTEN	NM_001304718.2	c.-384C>G		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.367C>G	p.His123Asp	missense_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 10, 2018	This sequence change replaces histidine with aspartic acid at codon 123 of the PTEN protein (p.His123Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Cowden syndrome (CS) associated tumors in a family (Invitae), and reported in an individual affected with CS (PMID: 11918710). ClinVar contains an entry for this variant (Variation ID: 428277). This variant falls in the conserved P-loop in the active site of the PTEN protein (PMID: 10555148). Experimental studies have shown that this missense change fully abrogated the PIP3 phosphatase activity of PTEN in a yeast assay (PMID: 21828076). Variants that disrupt the p.His123 amino acid residue in PTEN have been observed in affected individuals (PMID: 21828076, 10555148, 16619501, 10772829, 9256433, 9259288, 21291452, Invitae). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Nov 22, 2019	PTEN c.367C>G (p.His123Asp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PS3: Phosphatase activity <50% of wild type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 29706350, 21828076) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000580072.3) -

Cowden syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 27, 2020

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2016

The p.H123D variant (also known as c.367C>G), located in coding exon 5 of the PTEN gene, results from a C to G substitution at nucleotide position 367. The histidine at codon 123 is replaced by aspartic acid, an amino acid with similar properties. This alteration was previously detected in a 53-year-old female with a clinical diagnosis of Cowden syndrome (Bussaglia E et al. J. Invest. Dermatol., 2002 Apr;118:639-44). This alteration occurs in the PTEN phosphatase signature motif and in vivo functional studies performed in yeast demonstrated loss of intrinsic catalytic activity (Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.97		Gain of ubiquitination at K128 (P = 0.0388);
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		1.0

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

Other links and lift over

dbSNP: rs786204931; hg19: chr10-89692883; COSMIC: COSV64294365;