10-87933126-C-T

Position:

• chr10-87933126-C-T

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>T​(p.His123Tyr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H123D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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, 13 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 chr10-87933126-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 428277.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, 0.992
• PP5: Variant 10-87933126-C-T is Pathogenic according to our data. Variant chr10-87933126-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.367C>T	p.His123Tyr	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.886C>T	p.His296Tyr	missense_variant	6/10
PTEN	NM_001304718.2	c.-384C>T		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.367C>T	p.His123Tyr	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/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 27, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9256433, 10555148, 16619501, 21475810]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 05, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2023	Published functional studies demonstrate a damaging effect: absent phosphatase activity (Myers et al., 1997; Lee et al., 1999; Rodriguez-Escudero et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individual(s) with breast cancer (Evans et al., 2022); This variant is associated with the following publications: (PMID: 9256433, 16619501, 26681312, 10555148, 11448956, 21828076, 35426792, 19457929, 24475377, 32042934, 10772829) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 14, 2023	The PTEN c.367C>T (p.His123Tyr) variant has been reported in the published literature in an individual with breast cancer and a hematological malignancy (PMID: 26681312 (2015)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PTEN)). Published functional studies suggest that this variant is detrimental to normal PTEN protein function (PMID: 21828076 (2011), 10555148 (1998), 9256433 (1997)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

PTEN hamartoma tumor syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2018

In summary, this variant is a rare missense change that disrupts PTEN function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. The histidine 123 residue is known to be critical for PTEN protein function. Other missense substitutions at this position (His123Asp, His123Arg, His123Gln) also disrupt PTEN function and have been reported in individuals affected with Cowden syndrome (PMID: 11918710, 9259288, 21291452). This variant falls in the conserved P-loop in the active site of the PTEN protein (PMID: 10555148). Multiple experimental studies have shown that this variant abolishes PTEN kinase activity, and leads to cell proliferation, anchorage-independent growth, and loss of cell cycle progression inhibition (PMID: 21828076, 10555148, 16619501, 10772829, 9256433). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in the germline of individuals with a PTEN-related disease. ClinVar contains an entry for this variant (Variation ID: 189486). This sequence change replaces histidine with tyrosine at codon 123 of the PTEN protein (p.His123Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. -

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	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.92		Loss of methylation at K125 (P = 0.0668);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
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

LitVar

Other links and lift over

dbSNP: rs786204931; hg19: chr10-89692883; COSMIC: COSV64290794;