NM_000314.8(PTEN):c.1171C>T (p.Pro391Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 20, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000167422.8

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]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000218278	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 20, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 28250423, 29706350, 29785012, 30993208, 32442409 Citation Link,
SCV004357079	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 15, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29706350, 35089076, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000218278

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 20, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV004357079

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 15, 2022)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Prevalence of four Mendelian disorders associated with autism in 2392 affected families.

Saskin A, Fulginiti V, Birch AH, Trakadis Y.

J Hum Genet. 2017 Jun;62(6):657-659. doi: 10.1038/jhg.2017.16. Epub 2017 Mar 9.

PubMed [citation]

PMID:: 28250423

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 (7)

Details of each submission

From Ambry Genetics, SCV000218278.8

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

Description

The p.P391S variant (also known as c.1171C>T), located in coding exon 9 of the PTEN gene, results from a C to T substitution at nucleotide position 1171. The proline at codon 391 is replaced by serine, an amino acid with similar properties. This alteration was identified once in a large cohort of individuals diagnosed with autism spectrum disorder who underwent whole exome sequencing (Saskin A et al. J. Hum. Genet., 2017 Jun;62:657-659). This variant demonstrated possibly wildtype-like abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally neutral (Mighell TL et al. Am. J. Hum. Genet. 2018 05;102:943-955). In another functional study, this variant demonstrated PIP3 phosphatase activity and subcellular localization similar to PTEN wildtype (Mingo J et al. NPJ Precis Oncol, 2019 Apr;3:11). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV004357079.1

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

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 been reported in an individual affected with cancer (PMID: 35089076). 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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