10-87952134-G-T

Position:

• chr10-87952134-G-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.509G>T​(p.Ser170Ile) 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. 12/21 in silico tools predict a damaging 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. S170?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.46

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 helix (size 15) in uniprot entity PTEN_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) 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 chr10-87952135-T-R is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTEN. . Gene score misZ 3.4883 (greater than the threshold 3.09). Trascript score misZ 4.1129 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.96
• PP5: Variant 10-87952134-G-T is Pathogenic according to our data. Variant chr10-87952134-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 233590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.509G>T	p.Ser170Ile	missense_variant	6/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1028G>T	p.Ser343Ile	missense_variant	7/10		NP_001291646.4
PTEN	NM_001304718.2	c.-83G>T		5_prime_UTR_variant	6/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.509G>T	p.Ser170Ile	missense_variant	6/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2022

The PTEN c.509G>T variant is predicted to result in the amino acid substitution p.Ser170Ile. This variant has been reported in multiple individuals with Cowden syndrome (see for example - Table S2 - Tan et al. 2011. PubMed ID: 21194675; Ngeow et al. 2014. PubMed ID: 24778394). Additionally, different missense variants affecting this residue (p.Ser170Asn, p.Ser170Thr, p.Ser170Arg) have been reported as pathogenic (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2022

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 170 of the PTEN protein (p.Ser170Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS), collectively also known as PTEN hamartoma tumor syndrome (PMID: 21659347, 24778394; Invitae). ClinVar contains an entry for this variant (Variation ID: 233590). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects PTEN function (PMID: 29706350). This variant disrupts the p.Ser170 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10400993, 20712882, 21194675, 21659347, 23117110). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2018

The p.S170I pathogenic mutation (also known as c.509G>T), located in coding exon 6 of the PTEN gene, results from a G to T substitution at nucleotide position 509. The serine at codon 170 is replaced by isoleucine, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals meeting classic or relaxed diagnostic criteria for Cowden syndrome (Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Ngeow J et al. J. Clin. Oncol. 2014 Jun; 32(17):1818-24; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23(11):1538-43). Another mutation at the same position, p.S170R, has also been described in individuals meeting classic or relaxed criteria for Cowden syndrome (Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; de Leon MP et al. Dig Liver Dis 2013 Jan; 45(1):75-8). Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Ovarian neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.71		Loss of disorder (P = 0.0207);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.99

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: rs876660507; hg19: chr10-89711891; COSMIC: COSV64296946; COSMIC: COSV64296946;