10-87864514-A-T

Variant names:

• chr10-87864514-A-T
• rs1064794096
• NM_000314.8:c.45A>T

Variant summary

Our verdict is Pathogenic. The variant received 25 ACMG points: 25P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000314.8(PTEN):​c.45A>T​(p.Arg15Ser) variant causes a missense change. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.68
• Publications: 21 publications found

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]

PTEN Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 25 ACMG points.

• PS1: Transcript NM_000314.8 (PTEN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 36 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 chr10-87864513-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 428243.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 leiomyosarcoma, renal cell carcinoma, Cowden syndrome 1, macrocephaly-autism syndrome, glioma susceptibility 2, PTEN hamartoma tumor syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, activated PI3K-delta syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 10-87864514-A-T is Pathogenic according to our data. Variant chr10-87864514-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 419769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.45A>T	p.Arg15Ser	missense_variant	Exon 1 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.564A>T	p.Arg188Ser	missense_variant	Exon 2 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-661A>T		5_prime_UTR_variant	Exon 1 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.45A>T	p.Arg15Ser	missense_variant	Exon 1 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 15 of the PTEN protein (p.Arg15Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Cowden syndrome (PMID: 16773562, 21417916, 21659347, 24375884, 32037394). ClinVar contains an entry for this variant (Variation ID: 419769). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 17942903, 25875300, 29706350). This variant disrupts the p.Arg15 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16773562, 17942903, 21417916, 21659347, 24375884, 25875300, 29706350). 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. -

not provided Pathogenic:1

Feb 25, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed as a novo variant with confirmed parentage in a patient referred for testing at GeneDx and as an apparently de novo variant in a patient in the published literature with features consistent with PTEN-related hamartoma tumor syndrome (PMID: 24375884); Functional studies demonstrate the variant results in loss of lipid phosphatase and growth suppression activities and aberrant protein cellular localization (PMID: 25875300, 9823298, 29706350); 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; This variant is associated with the following publications: (PMID: 21103049, 21659347, 25875300, 9823298, 17213812, 16773562, 17942903, 10416987, 21417916, 24375884, 31447099, 24475377, 36591942, 29785012, 29706350) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 24, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R15S pathogenic mutation (also known as c.45A>T), located in coding exon 1 of the PTEN gene, results from an A to T substitution at nucleotide position 45. The arginine at codon 15 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in several individuals with PTEN-related features (Pilarski R et al. J Med Genet. 2011 Aug;48:505-12; Nagy R et al. Thyroid. 2011 May;21:505-10; Sarquis MS et al. Am J Hum Genet. 2006 Jul;79:23-30). This alteration was confirmed de novo in an 18-month-old with significant macrocephaly, motor skill developmental delays, and posterior periventricular multifocal white matter abnormalities (Vanderver A et al. Am J Med Genet A. 2014 Mar;164A:627-33). A different alteration leading to the same amino acid substitution, c.45A>C (p.R15S), has been described in individuals with PTEN-related features (Reuter MS et al. Genet Med, 2020 Jun;22:1015-1024; Ambry internal data). In a functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet. 2018 05;102:943-955). Additional functional studies have demonstrated wildtype-like protein stability but significantly reduced phosphatase activity (Andrés-Pons A et al. Cancer Res. 2007 Oct;67:9731-9; Gil A et al. PLoS One 2015 Apr;10(4):e0119287; Mingo J et al. Eur J Hum Genet. 2018 08;26:1180-1187). 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). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.14	B
Vest4		0.95
MutPred		0.52		Loss of MoRF binding (P = 0.0341);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.99
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064794096; hg19: chr10-89624271; COSMIC: COSV64290416;