chr10-87952258-C-G

Variant names:

• chr10-87952258-C-G
• rs121909232
• NM_000314.8:c.633C>G

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PP2 PS4_Moderate PM2 PS2

This summary comes from the ClinGen Evidence Repository: PTEN c.633C>G (p.Cys211Trp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (internal laboratory contributor(s) SCV000329477.6)PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 24375884, internal laboratory contributor(s) SCV000329477.6)PM2: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603125/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense, splice_region
• Scores: Splicing: ADA: 0.9829
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 5.72
• Publications: 23 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 9 ACMG points.

• PS2: 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.633C>G	p.Cys211Trp	missense splice_region	Exon 6 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.1152C>G	p.Cys384Trp	missense splice_region	Exon 7 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.42C>G	p.Cys14Trp	missense splice_region	Exon 6 of 9	NP_001291647.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.633C>G	p.Cys211Trp	missense splice_region	Exon 6 of 9	ENSP00000361021.3
	PTEN	ENST00000693560.1		c.1152C>G	p.Cys384Trp	missense splice_region	Exon 7 of 10	ENSP00000509861.1
	PTEN	ENST00000700029.2		c.633C>G	p.Cys211Trp	missense splice_region	Exon 6 of 10	ENSP00000514759.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2 Uncertain:1

Jan 10, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 03, 2025

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.633C>G (p.Cys211Trp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2_VS: Three pediatric patients (Internal lab contribution) confirmed de novo with WES trio. PP3: REVEL score >.7 (Score: 0.856). PS4_P: Vanderver et al (PMID 24375884) patient #21 with macrocephaly, developmental delay, and enlarged periventricular spaces. Phenotype score of +6, +1 proband point. Confirmed de novo pediatric patient with extreme macrocephaly (+4 SD), developmental delay, hemihypertrophy, autism and ID (Internal laboratory contribution). Phenotype score +5, +1 proband point. PM2_P: Absent in large sequenced populations (gnomad v4). 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.

Mar 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 211 of the PTEN protein (p.Cys211Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with macrocephaly, mild developmental delay, and autism spectrum characteristics (PMID: 24375884, 33767182). ClinVar contains an entry for this variant (Variation ID: 279878). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 32350270). 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.

not provided Pathogenic:1

Sep 14, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: impaired protein stability and increased pAKT levels, wildtype-like phosphatase activity (Mighell 2018, Post 2020); This variant is associated with the following publications: (PMID: 18626510, 25527629, 24375884, 27732747, 29706350, 32350270)

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C211W variant (also known as c.633C>G), located in coding exon 6 of the PTEN gene, results from a C to G substitution at nucleotide position 633. The cysteine at codon 211 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been identified in an individual with features of PTEN hamartoma tumor syndrome (PHTS) (Vanderver A et al. Am. J. Med. Genet. A, 2014 Mar;164A:627-33). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.91		Gain of sheet (P = 0.0344)
MVP		0.98
MPC		2.6
ClinPred		0.99	D
GERP RS		5.8
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.96
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.91
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: rs121909232; hg19: chr10-89712015;