NM_000314.8:c.45A>T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 29 ACMG points: 29P and 0B. PS1_Very_Strong PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000567809: Functional studies demonstrate the variant results in loss of lipid phosphatase and growth suppression activities and aberrant protein cellular localization (PMID:25875300, 9823298, 29706350)" and additional evidence is available in ClinVar. 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. R15I) has been classified as Uncertain significance.

• 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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 29 ACMG points.

• PS1: Transcript NM_000314.8 (PTEN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000567809: Functional studies demonstrate the variant results in loss of lipid phosphatase and growth suppression activities and aberrant protein cellular localization (PMID: 25875300, 9823298, 29706350); SCV001211259: Experimental studies have shown that this missense change affects PTEN function (PMID: 17942903, 25875300, 29706350).; SCV004001638: "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)."
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 37 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 Cowden syndrome 1, PTEN hamartoma tumor syndrome, macrocephaly-autism syndrome, glioma susceptibility 2, activated PI3K-delta syndrome, Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, leiomyosarcoma, Cowden disease, renal cell carcinoma, Proteus-like 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.45A>T	p.Arg15Ser	missense	Exon 1 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.564A>T	p.Arg188Ser	missense	Exon 2 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.-661A>T		5_prime_UTR	Exon 1 of 9	NP_001291647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.45A>T	p.Arg15Ser	missense	Exon 1 of 9	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.564A>T	p.Arg188Ser	missense	Exon 2 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.45A>T	p.Arg15Ser	missense	Exon 1 of 10	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)
1	-	-	PTEN hamartoma tumor syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;