NM_000314.8(PTEN):c.1066A>G (p.Asn356Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 20, 2023
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:: RCV000131284.11

Allele description [Variation Report for NM_000314.8(PTEN):c.1066A>G (p.Asn356Asp)]

NM_000314.8(PTEN):c.1066A>G (p.Asn356Asp)

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.1066A>G (p.Asn356Asp)

HGVS:

NC_000010.11:g.87965326A>G
NG_007466.2:g.106888A>G
NM_000314.8:c.1066A>GMANE SELECT
NM_001304717.5:c.1585A>G
NM_001304718.2:c.475A>G
NP_000305.3:p.Asn356Asp
NP_001291646.4:p.Asn529Asp
NP_001291647.1:p.Asn159Asp
LRG_311t1:c.1066A>G
LRG_311:g.106888A>G
NC_000010.10:g.89725083A>G
NM_000314.4:c.1066A>G
NM_000314.6:c.1066A>G
p.N356D

Protein change:

N159D

Links:

dbSNP: rs587782345

NCBI 1000 Genomes Browser:

rs587782345

Molecular consequence:

NM_000314.8:c.1066A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001304717.5:c.1585A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001304718.2:c.475A>G - 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
SCV000186253	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 20, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15769473, 24656772, 25669429, 29706350, 31006514 Citation Link,
SCV000691140	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 5, 2019)	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

SCV000186253

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 20, 2023)

germline

clinical testing

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

Citation Link,

SCV000691140

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 5, 2019)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The pairwise energy content estimated from amino acid composition discriminates between folded and intrinsically unstructured proteins.

Dosztányi Z, Csizmók V, Tompa P, Simon I.

J Mol Biol. 2005 Apr 8;347(4):827-39.

PubMed [citation]

PMID:: 15769473

SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer.

Li G, Ci W, Karmakar S, Chen K, Dhar R, Fan Z, Guo Z, Zhang J, Ke Y, Wang L, Zhuang M, Hu S, Li X, Zhou L, Li X, Calabrese MF, Watson ER, Prasad SM, Rinker-Schaeffer C, Eggener SE, Stricker T, Tian Y, et al.

Cancer Cell. 2014 Apr 14;25(4):455-68. doi: 10.1016/j.ccr.2014.02.007. Epub 2014 Mar 20.

PubMed [citation]

PMID:: 24656772
PMCID:: PMC4443692

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000186253.11

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

Description

The p.N356D variant (also known as c.1066A>G), located in coding exon 9 of the PTEN gene, results from an A to G substitution at nucleotide position 1066. The asparagine at codon 356 is replaced by aspartic acid, 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 wild type-like (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). Based on internal structural analysis, this alteration is in a solvent exposed, unstructured portion of the protein, is associated with low free energy change, and is not known to be involved in any interactions; therefore, the change from asparagine to aspartic acid (a change from neutral to negative) is not expected to have a significant functional effect (Dosztányi Z et al. J. Mol. Biol., 2005 Apr;347:827-39; Li G et al. Cancer Cell, 2014 Apr;25:455-68). This alteration has been reported as a pathogenic mutation in multiple publications from the same research group (Mester JL et al. Eur. J. Hum. Genet. 2011 Jul;19(7):763-8; Ngeow J et al. J. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2063-71; Tan MH et al. Am. J. Hum. Genet. 2011 Jan;88(1):42-56; Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). This amino acid position is highly 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, SCV000691140.3

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

#	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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