NM_000314.8(PTEN):c.698G>A (p.Arg233Gln) AND PTEN hamartoma tumor syndrome

Clinical significance:Uncertain significance (Last evaluated: Mar 5, 2019)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000473076.2

Allele description [Variation Report for NM_000314.8(PTEN):c.698G>A (p.Arg233Gln)]

NM_000314.8(PTEN):c.698G>A (p.Arg233Gln)

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.698G>A (p.Arg233Gln)
Other names:
NM_000314.6(PTEN):c.698G>A
HGVS:
  • NC_000010.11:g.87957916G>A
  • NG_007466.2:g.99478G>A
  • NM_000314.8:c.698G>AMANE SELECT
  • NM_001304717.5:c.1217G>A
  • NM_001304718.2:c.107G>A
  • NP_000305.3:p.Arg233Gln
  • NP_001291646.4:p.Arg406Gln
  • NP_001291647.1:p.Arg36Gln
  • LRG_311t1:c.698G>A
  • LRG_311:g.99478G>A
  • NC_000010.10:g.89717673G>A
  • NM_000314.4:c.698G>A
Protein change:
R233Q
Links:
dbSNP: rs770025422
NCBI 1000 Genomes Browser:
rs770025422
Molecular consequence:
  • NM_000314.8:c.698G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001304717.5:c.1217G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001304718.2:c.107G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
PTEN hamartoma tumor syndrome (PHTS)
Synonyms:
PTEN Hamartomatous Tumour Syndrome
Identifiers:
MONDO: MONDO:0017623; MedGen: C1959582

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000541600Invitaecriteria provided, single submitter
Uncertain significance
(Jul 12, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000930128ClinGen PTEN Variant Curation Expert Panelreviewed by expert panel
Uncertain significance
(Mar 5, 2019)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

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
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000541600.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces arginine with glutamine at codon 233 of the PTEN protein (p.Arg233Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs770025422, ExAC <0.01%) but has not been reported in the literature in individuals with a PTEN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen PTEN Variant Curation Expert Panel, SCV000930128.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

PTEN c.698G>A (p.R233Q) 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_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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