NM_000314.7(PTEN):c.235G>A (p.Ala79Thr) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jan 18, 2018
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:: RCV000034594.1

Allele description

NM_000314.7(PTEN):c.235G>A (p.Ala79Thr)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_000314.7(PTEN):c.235G>A (p.Ala79Thr)

Other names:

p.A79T:GCC>ACC; NM_000314.6(PTEN):c.235G>A(p.Ala79Thr)

HGVS:

NC_000010.11:g.87931071G>A
NG_007466.2:g.72633G>A
NM_000314.7:c.235G>A
NM_001304717.5:c.754G>A
NM_001304718.1:c.-516G>A
NP_000305.3:p.Ala79Thr
NP_001291646.4:p.Ala252Thr
LRG_311t1:c.235G>A
LRG_311:g.72633G>A
LRG_311p1:p.Ala79Thr
NC_000010.10:g.89690828G>A
NG_007466.2:c.235G>A
NM_000314.4:c.235G>A
NM_000314.6:c.235G>A
NM_001304717.2:c.754G>A
NP_001291646.2:p.Ala252Thr
p.A79T

Protein change:

A252T

Links:

dbSNP: rs202004587

NCBI 1000 Genomes Browser:

rs202004587

Molecular consequence:

NM_001304718.1:c.-516G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000314.6:c.235G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

variation affecting protein function [Variation Ontology: 0003]

Condition(s)

Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000043462	Biesecker Lab/Human Development Section,National Institutes of Health - ClinSeq	no assertion criteria provided	variant of unknown significance (Jul 13, 2012)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000222198	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Dec 11, 2017)	germline	clinical testing	Citation Link,
SCV000806056	PreventionGenetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 18, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000888591	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest pathogenicity assessment criteria)	Uncertain significance (Jan 18, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	2	not provided	not provided	571	not provided	research

Citations

PubMed

Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.

Johnston JJ, Rubinstein WS, Facio FM, Ng D, Singh LN, Teer JK, Mullikin JC, Biesecker LG.

Am J Hum Genet. 2012 Jul 13;91(1):97-108. doi: 10.1016/j.ajhg.2012.05.021. Epub 2012 Jun 14.

PubMed [citation]

PMID:: 22703879
PMCID:: PMC3397257

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (3)

Details of each submission

From Biesecker Lab/Human Development Section,National Institutes of Health - ClinSeq, SCV000043462.1

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

Description

The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See PubMed ID:22703879 for details.

Description

Converted during submission to Uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	571	not provided	discovery		2	not provided	not provided	not provided

From GeneDx, SCV000222198.12

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

Description

This variant is denoted PTEN c.235G>A at the cDNA level, p.Ala79Thr (A79T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has been observed in at least four individuals with varying cancer histories; however, only one is reported to meet full International Cowden Syndrome Consortium operational diagnostic criteria (Tengs 2006, Mester 2011, Ngeow 2011, Pilarski 2011, Tan 2011). This variant was also observed in at least two individuals with Cowden syndrome or Cowden-like syndrome, with no specific information about cancer history (Nizialek 2015, Chen 2017). Additionally, PTEN Ala79Thr was observed in 2 of 571 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012) and in one individual undergoing multigene panel testing due to a personal history suggestive of a hereditary colorectal cancer syndrome (Yurgelun 2015). PTEN Ala79Thr was observed at an allele frequency of 0.02% (5/30734) in individuals of South Asian ancestry in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN Ala79Thr is located within the Phosphatase domain (Molinari 2014). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether PTEN Ala79Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

From PreventionGenetics, SCV000806056.1

#	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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000888591.1

#	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: Jul 8, 2019

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