10-87957958-T-C

Position:

• chr10-87957958-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP2 PP3 PS3_Moderate PM6_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: PTEN c.740T>C (p.Leu247Ser) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_Supporting: Absent in large sequenced populations (PMID:27535533).PM6_Strong: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMIDs: 28086757 and 29752200)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.PS3_Moderate: Functional studies showing a damaging effect on protein function. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID:29706350). This variant: score of -1.669765892.PP3: REVEL score > 0.7 (this variant: score=0.918). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16044135/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.62

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.740T>C	p.Leu247Ser	missense_variant	7/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1259T>C	p.Leu420Ser	missense_variant	8/10		NP_001291646.4
PTEN	NM_001304718.2	c.149T>C	p.Leu50Ser	missense_variant	7/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.740T>C	p.Leu247Ser	missense_variant	7/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Aug 04, 2023

PTEN c.740T>C (p.Leu247Ser) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2_Supporting: Absent in large sequenced populations (PMID: 27535533). PM6_Strong: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMIDs: 28086757 and 29752200) 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. PS3_Moderate: Functional studies showing a damaging effect on protein function. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of -1.669765892. PP3: REVEL score > 0.7 (this variant: score=0.918). -

Macrocephaly-autism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences

Nov 01, 2015

Patient, a 4 year-old girl, showed mild developmental delay, hypotonia, and dysmorphic facial features. Her last head circumference was 56.5 cm (+4.0SD). This mutation was confirmed de novo. The expression level of phosphorylated S6 ribosomal protein in her lymphoblastoid cell line was elevated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.1	D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.74		Loss of catalytic residue at L247 (P = 0.0355);.;
MVP		0.96
MPC		2.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.87
gMVP		0.97

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: rs1057519368; hg19: chr10-89717715; COSMIC: COSV64302434;