NM_000314.8(PTEN):c.1171C>T (p.Pro391Ser) AND PTEN hamartoma tumor syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Mar 23, 2020
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:: RCV000538790.11

Allele description [Variation Report for NM_000314.8(PTEN):c.1171C>T (p.Pro391Ser)]

NM_000314.8(PTEN):c.1171C>T (p.Pro391Ser)

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.1171C>T (p.Pro391Ser)

Other names:

p.P391S:CCT>TCT; NM_000314.6(PTEN):c.1171C>T(p.Pro391Ser)

HGVS:

NC_000010.11:g.87965431C>T
NG_007466.2:g.106993C>T
NM_000314.8:c.1171C>TMANE SELECT
NM_001304717.5:c.1690C>T
NM_001304718.2:c.580C>T
NP_000305.3:p.Pro391Ser
NP_001291646.4:p.Pro564Ser
NP_001291647.1:p.Pro194Ser
LRG_311t1:c.1171C>T
LRG_311:g.106993C>T
NC_000010.10:g.89725188C>T
NM_000314.4:c.1171C>T
NM_000314.6(PTEN):c.1171C>T
p.P391S
p.Pro391Ser

Protein change:

P194S

Links:

dbSNP: rs786203911

NCBI 1000 Genomes Browser:

rs786203911

Molecular consequence:

NM_000314.8:c.1171C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001304717.5:c.1690C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001304718.2:c.580C>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000645550	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 23, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29706350, 29785012, 30993208, 28492532
SCV000840495	Clingen PTEN Variant Curation Expert Panel, Clingen	reviewed by expert panel (ClinGen PTEN ACMG Specifications v2)	Uncertain significance (Mar 23, 2020)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 30993208, 29706350, 29785012, 27535533 Citation Link,
SCV004838613	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 (2) [See all records that cite these PMIDs] 29706350, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000645550

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 23, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000840495

Clingen PTEN Variant Curation Expert Panel, Clingen

reviewed by expert panel

(ClinGen PTEN ACMG Specifications v2)

Uncertain significance
(Mar 23, 2020)

germline

curation

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV004838613

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 (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	7	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Precise definition of PTEN C-terminal epitopes and its implications in clinical oncology.

Mingo J, Luna S, Gaafar A, Nunes-Xavier CE, Torices L, Mosteiro L, Ruiz R, Guerra I, Llarena R, Angulo JC, López JI, Pulido R.

NPJ Precis Oncol. 2019;3:11. doi: 10.1038/s41698-019-0083-4.

PubMed [citation]

PMID:: 30993208
PMCID:: PMC6465295

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000645550.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 391 of the PTEN protein (p.Pro391Ser). This variant is present in population databases (rs786203911, gnomAD 0.0009%). 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: 187673). 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, 30993208). 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, SCV000840495.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

Description

PTEN c.1171C>T (p.Pro391Ser) PTEN c.1171C>T (p.Pro391Ser) 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: 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. BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 30993208, 29785012, 29706350)

#	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, SCV004838613.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces proline with serine at codon 391 of the PTEN protein. Functional studies have reported this variant does not significantly affect PTEN protein function (PMID: 29706350). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/243908 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		7	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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