NM_000314.8(PTEN):c.745G>A (p.Val249Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 24, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002388751.3

Allele description [Variation Report for NM_000314.8(PTEN):c.745G>A (p.Val249Met)]

NM_000314.8(PTEN):c.745G>A (p.Val249Met)

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.745G>A (p.Val249Met)

HGVS:

NC_000010.11:g.87957963G>A
NG_007466.2:g.99525G>A
NM_000314.8:c.745G>AMANE SELECT
NM_001304717.5:c.1264G>A
NM_001304718.2:c.154G>A
NP_000305.3:p.Val249Met
NP_001291646.4:p.Val422Met
NP_001291647.1:p.Val52Met
LRG_311t1:c.745G>A
LRG_311:g.99525G>A
NC_000010.10:g.89717720G>A
NM_000314.4:c.745G>A

Protein change:

V249M

Links:

dbSNP: rs2132277398

NCBI 1000 Genomes Browser:

rs2132277398

Molecular consequence:

NM_000314.8:c.745G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001304717.5:c.1264G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001304718.2:c.154G>A - 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
SCV002671715	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29706350, 29785012 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002671715

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 24, 2023)

germline

clinical testing

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

Citation Link

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

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

Details of each submission

From Ambry Genetics, SCV002671715.3

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

Description

The p.V249M variant (also known as c.745G>A), located in coding exon 7 of the PTEN gene, results from a G to A substitution at nucleotide position 745. The valine at codon 249 is replaced by methionine, an amino acid with highly similar properties. This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882) but had wildtype-like phosphatase activity in a massively parallel functional assay using a humanized yeast model (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Last Updated: Sep 29, 2024

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