10-87957940-T-C

Position:

• chr10-87957940-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PP2 PS3_Moderate PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.722T>C (p.Phe241Ser) variant 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). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:15805158).PM2_P: Absent in large sequenced populations (PMID 27535533).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.PP3: REVEL score > 0.7 (score=0.858). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000555/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.722T>C	p.Phe241Ser	missense_variant	7/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1241T>C	p.Phe414Ser	missense_variant	8/10		NP_001291646.4
PTEN	NM_001304718.2	c.131T>C	p.Phe44Ser	missense_variant	7/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.722T>C	p.Phe241Ser	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:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 14, 2023	NM_000314.8(PTEN):c.722T>C (p.Phe241Ser) variant 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). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:15805158). PM2_P: Absent in large sequenced populations (PMID 27535533). 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. PP3: REVEL score > 0.7 (score=0.858). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 03, 2017	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change creates an unstable protein and partially affects the phosphatase activity of the PTEN protein (PMID: 21828076, 25527629).  An additional study showed that this variant fails to suppress tyrosine hydroxylase activity in mouse PC12 cells (PMID: 26579216). This variant has been reported in an individual affected with autism and macrocephaly (PMID: 15805158). ClinVar contains an entry for this variant (Variation ID: 7850). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 241 of the PTEN protein (p.Phe241Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2022

Published functional studies demonstrate a damaging effect: reduced lipid phosphatase activity, protein abundance, and nuclear localization (Rodriguez-Escudero et al., 2011; Mighell et al., 2018; Matreyek et al., 2018; Wong et al., 2020); 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: 25527629, 29373119, 26579216, 32190315, 29706350, 29455665, 31086789, 29505425, 29785012, 23379765, 18728070, 32150788, 27535533, 24851117, 21828076, 18626510, 15805158) -

Macrocephaly-autism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.0073	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D;.
REVEL	Pathogenic	0.86
Sift	Benign	0.14	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.065	B;.
Vest4		0.95
MutPred		0.72		Loss of sheet (P = 0.0104);.;
MVP		0.98
MPC		1.9
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.98

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: rs121909240; hg19: chr10-89717697; COSMIC: COSV64294827;