NM_000314.8(PTEN):c.1093G>A (p.Val365Ile) AND PTEN hamartoma tumor syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 1, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000228413.16

Allele description [Variation Report for NM_000314.8(PTEN):c.1093G>A (p.Val365Ile)]

NM_000314.8(PTEN):c.1093G>A (p.Val365Ile)

Gene:

PTEN:phosphatase and tensin homolog [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_000314.8(PTEN):c.1093G>A (p.Val365Ile)

Other names:

NM_000314.7(PTEN):c.1093G>A

HGVS:

NC_000010.11:g.87965353G>A
NG_007466.2:g.106915G>A
NM_000314.8:c.1093G>AMANE SELECT
NM_001304717.5:c.1612G>A
NM_001304718.2:c.502G>A
NP_000305.3:p.Val365Ile
NP_001291646.4:p.Val538Ile
NP_001291647.1:p.Val168Ile
LRG_311t1:c.1093G>A
LRG_311:g.106915G>A
NC_000010.10:g.89725110G>A
NM_000314.4:c.1093G>A
NM_000314.6:c.1093G>A

Protein change:

V168I

Links:

dbSNP: rs758542021

NCBI 1000 Genomes Browser:

rs758542021

Molecular consequence:

NM_000314.8:c.1093G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001304717.5:c.1612G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001304718.2:c.502G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: PTEN hamartoma tumor syndrome (PHTS)
Synonyms:: PTEN Hamartomatous Tumour Syndrome
Identifiers:: MONDO: MONDO:0017623; MeSH: D006223; MedGen: C1959582

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Chain B, U5 small nuclear ribonucleoprotein 200 kDa helicase
Chain B, U5 small nuclear ribonucleoprotein 200 kDa helicase
gi|1802444721|pdb|6S8Q|B

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000284581	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29706350, 29785012, 28492532
SCV000930120	Clingen PTEN Variant Curation Expert Panel, Clingen	reviewed by expert panel (ClinGen PTEN ACMG Specifications V3)	Uncertain significance (Dec 1, 2023)	germline	curation	Citation Link,
SCV004838607	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000284581

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000930120

Clingen PTEN Variant Curation Expert Panel, Clingen

reviewed by expert panel

(ClinGen PTEN ACMG Specifications V3)

Uncertain significance
(Dec 1, 2023)

germline

curation

Citation Link,

SCV004838607

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships.

Mighell TL, Evans-Dutson S, O'Roak BJ.

Am J Hum Genet. 2018 May 3;102(5):943-955. doi: 10.1016/j.ajhg.2018.03.018. Epub 2018 Apr 26.

PubMed [citation]

PMID:: 29706350
PMCID:: PMC5986715

Multiplex assessment of protein variant abundance by massively parallel sequencing.

Matreyek KA, Starita LM, Stephany JJ, Martin B, Chiasson MA, Gray VE, Kircher M, Khechaduri A, Dines JN, Hause RJ, Bhatia S, Evans WE, Relling MV, Yang W, Shendure J, Fowler DM.

Nat Genet. 2018 Jun;50(6):874-882. doi: 10.1038/s41588-018-0122-z. Epub 2018 May 21.

PubMed [citation]

PMID:: 29785012
PMCID:: PMC5980760

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000284581.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 365 of the PTEN protein (p.Val365Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 237639). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350, 29785012). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clingen PTEN Variant Curation Expert Panel, Clingen, SCV000930120.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

PTEN c.1093G>A (p.Val365Ile) is currently classified as a variant of uncertain significance 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: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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. BP4: REVEL score < 0.5 (score=0.441) Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting and 2 pathogenic supporting codes get -1 + (1*2) points; total is 1 (VUS).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004838607.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces valine with isoleucine at codon 365 of the PTEN protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/239418 chromosomes 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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