rs587780007

Variant names:

• chr10-87961006-G-A
• rs587780007
• NM_000314.8:c.914G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-87961006-G-A
• chr10-87961006-G-C
• chr10-87961006-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PP2 BS3_Supporting PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.914G>A (p.S305N) is currently classified as a variant of uncertain significance 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).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.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000632/MONDO:0017623/003

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:14
• Conservation: PhyloP100: 5.66
• Publications: 9 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.914G>A	p.Ser305Asn	missense_variant	Exon 8 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1433G>A	p.Ser478Asn	missense_variant	Exon 9 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.323G>A	p.Ser108Asn	missense_variant	Exon 8 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.914G>A	p.Ser305Asn	missense_variant	Exon 8 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461620 Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111870

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: reviewed by expert panel

Submissions by phenotype

Cowden syndrome 1 Uncertain:3

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

May 23, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 17, 2025

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTEN c.914G>A p.(Ser305Asn) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function. This variant was reported to behave similar to wild-type in a functional study (PMID: 29706350). To our knowledge, this variant has not been reported in individuals with PTEN hamartoma tumor syndromes. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

PTEN hamartoma tumor syndrome Uncertain:3

Apr 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with asparagine at codon 305 of the PTEN protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 305 of the PTEN protein (p.Ser305Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital hydrocephalus (PMID: 33077954). ClinVar contains an entry for this variant (Variation ID: 127696). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350). 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. -

Mar 05, 2019

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.914G>A (p.S305N) is currently classified as a variant of uncertain significance 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). 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. BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) -

Hereditary cancer-predisposing syndrome Uncertain:3

Oct 19, 2020

Yale Center for Mendelian Genomics, Yale University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S305N variant (also known as c.914G>A), located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide position 914. The serine at codon 305 is replaced by asparagine, an amino acid with highly similar properties. In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was wildtype-like (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). In a cohort of 381 patients with congenital hydrocephalus, who underwent whole-exome sequencing, this variant was identified in one proband with macrocephaly, cerebellar tonsillar ectopia, and neurodevelopment delay; this patient had no previous clinical diagnosis of PTEN hamartoma tumor syndrome (Jin SC et al. Nat Med, 2020 Nov;26:1754-1765).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Mar 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with asparagine at codon 305 of the PTEN protein. In a massively parallel functional assay, this variant did not demonstrate a significant defect in lipid phosphatase activity (PMID: 29706350). In a cohort of individuals affected with congenital hydrocephalus, this variant was reported in an individual affected with macrocephaly, cerebellar tonsillar ectopia and neurodevelopmental delay (PMID: 33077954). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Apr 15, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PTEN c.914G>A (p.Ser305Asn) results in a conservative amino acid change located in the Tensin phosphatase, C2 domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251274 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.914G>A has been reported in the literature in an individual affected with non-small cell lung cancer who also carried an EGFR del19 mutation which is associated with responsiveness to Tyrosine kinase inhibitors (example: Kim_2014). This variant has also been identified as an inherited variant in an individual with aqueductal stenosis, macrocephaly, cerebellar tonsillar ectopia and neurodevelopmental delay through WES (example: Jin_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function through a large-scale in vitro assay (Mighell_2018). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 33077954, 24468202, 29706350, 15492994). ClinVar contains an entry for this variant (Variation ID: 127696). Based on the evidence outlined above, the variant was classified as uncertain significance. -

PTEN-related disorder Uncertain:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTEN c.914G>A variant is predicted to result in the amino acid substitution p.Ser305Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Sep 26, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with congenital hydrocephalus, macrocephaly, cerebellar tonsillar ectopia, and neurodevelopmental delay (PMID: 33077954); Published functional studies demonstrate wildtype-like phosphatase activity (PMID: 29706350); This variant is associated with the following publications: (PMID: 24468202, 15492994, 33077954, 29706350, 18626510, 38439105) -

Glioma susceptibility 2 Uncertain:1

Mar 06, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Prostate cancer;C1848599:VACTERL with hydrocephalus;C1854416:Macrocephaly-autism syndrome;C1959582:PTEN hamartoma tumor syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		5.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.16	N;.
REVEL	Benign	0.26
Sift	Benign	0.23	T;.
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;.
Vest4		0.58
MutPred		0.35		Loss of phosphorylation at S305 (P = 0.0302);.;
MVP		0.85
MPC		1.1
ClinPred		0.77	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.60
Mutation Taster		=68/32	polymorphism

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: rs587780007; hg19: chr10-89720763;