NM_000314.8:c.314G>A

Variant names:

• chr10-87933073-G-A
• rs587782343
• NM_000314.8:c.314G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP2 PS4_Supporting PM2 PM6

This summary comes from the ClinGen Evidence Repository: PTEN c.314G>A (p.Cys105Tyr) meets criteria to be classified as likely 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).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957)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.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor ClinVar Organization ID 26957) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000393/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 9.52
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: 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.

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.314G>A	p.Cys105Tyr	missense	Exon 5 of 9	NP_000305.3
	PTEN	NM_001304718.2		c.-437G>A		5_prime_UTR_premature_start_codon_gain	Exon 4 of 9	NP_001291647.1
	PTEN	NM_001304717.5		c.833G>A	p.Cys278Tyr	missense	Exon 6 of 10	NP_001291646.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.314G>A	p.Cys105Tyr	missense	Exon 5 of 9	ENSP00000361021.3
	PTEN	ENST00000693560.1		c.833G>A	p.Cys278Tyr	missense	Exon 6 of 10	ENSP00000509861.1
	PTEN	ENST00000700029.2		c.314G>A	p.Cys105Tyr	missense	Exon 5 of 10	ENSP00000514759.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

May 10, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTEN c.314G>A (p.Cys105Tyr) variant was identified at a near heterozygous allelic fraction of 49.3%, a frequency which may be consistent with it being of germline origin. This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. It has been reported in a patient with Bannayan-Riley-Ruvalcaba syndrome (BRRS) (Marsh DJ et al., PMID: 10400993). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic germline variant by three submitters, including an expert panel (ClinVar ID: 142261). Other variants in the same codon, (p.Cys105Arg, p.Cys105Gly), have been reported in affected individuals and are considered pathogenic/likely pathogenic (ClinVar IDs: 2628372, 1728081). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PTEN function. In vitro and in vivo functional studies show that this variant has a damaging effect on both lipid phosphatase activity of PTEN and the binding of PTEN to LKB1, indicating that this variant impacts protein function (Mehenni H et al., PMID: 15987703; Park HEH et al., PMID: 34561453). The PTEN gene is defined by the ClinGen PTEN Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Mester JL et al., PMID: 30311380). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), and gene-specific practices from the ClinGen Criteria Specification Registry (Mester JL et al., PMID: 30311380), the PTEN c.314G>A (p.Cys105Tyr) variant is classified as pathogenic.

Apr 16, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTEN hamartoma tumor syndrome Pathogenic:2

Jun 04, 2021

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.314G>A (p.Cys105Tyr) meets criteria to be classified as likely 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). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor ClinVar Organization ID 26957)

Oct 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 105 of the PTEN protein (p.Cys105Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Bannayan-Riley-Ruvalcaba syndrome and/or PTEN-related conditions (PMID: 10400993; Invitae; external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 142261). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 15987703). For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 30, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C105Y variant (also known as c.314G>A) is located in coding exon 5 of the PTEN gene. This alteration results from a G to A substitution at nucleotide position 314. The cysteine at codon 105 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was observed in 1 of 43 individuals who were clinically diagnosed with Bannayan-Riley-Ruvalcaba (BRR) syndrome (Marsh DJ et al. Hum Mol Genet., 1999 Aug;8(8):1461-72). In addition, this alteration has been observed in one individual with a personal and/or family history that is consistent with PTEN hamartoma tumor syndrome, where the variant was determined to be the result of a de novo mutation or germline mosaicism, although paternity was not confirmed (Ambry internal data, interlaboratory communication). In one functional study, the PTEN p.C105Y variant showed no interaction with the LKB1 (STK11) protein in a yeast two-hybrid assay (Mehenni H et al. Hum. Mol. Genet., 2005 Aug;14:2209-19). Based on internal structural analysis, C105Y is more disruptive to the phosphatase domain than all nearby internally pathogenic variants, including one at the same position (Dempsey DR et al. Nat Struct Mol Biol., 2021 10;28(10):858-868; Lee CU et al. Angew Chem Int Ed Engl., 2015 Nov;54(46):13796-800). 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 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010). Furthermore, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.84		Gain of phosphorylation at C105 (P = 0.0879)
MVP		0.98
MPC		3.0
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	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: rs587782343; hg19: chr10-89692830; COSMIC: COSV64290665;