NM_000314.8(PTEN):c.80A>G (p.Tyr27Cys) AND PTEN hamartoma tumor syndrome

Clinical significance:Likely pathogenic (Last evaluated: Nov 22, 2019)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000314.8(PTEN):c.80A>G (p.Tyr27Cys)]

NM_000314.8(PTEN):c.80A>G (p.Tyr27Cys)

PTEN:phosphatase and tensin homolog [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000314.8(PTEN):c.80A>G (p.Tyr27Cys)
  • NC_000010.11:g.87894025A>G
  • NC_000010.11:g.87894025A>G
  • NG_007466.2:g.35587A>G
  • NM_000314.8:c.80A>GMANE SELECT
  • NM_001304717.5:c.599A>G
  • NM_001304718.2:c.-626A>G
  • NP_000305.3:p.Tyr27Cys
  • NP_001291646.4:p.Tyr200Cys
  • LRG_311t1:c.80A>G
  • LRG_311:g.35587A>G
  • NC_000010.10:g.89653782A>G
  • NM_000314.4:c.80A>G
  • NM_000314.7(PTEN):c.80A>G
  • p.Tyr27Cys
Protein change:
dbSNP: rs886041877
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001304718.2:c.-626A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000314.8:c.80A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001304717.5:c.599A>G - missense variant - [Sequence Ontology: SO:0001583]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000541611Invitaecriteria provided, single submitter
Uncertain significance
(Nov 12, 2016)
germlineclinical testing

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

SCV001244234ClinGen PTEN Variant Curation Expert Panelreviewed by expert panel
Likely pathogenic
(Nov 22, 2019)

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



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]

Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations.

Vanderver A, Tonduti D, Kahn I, Schmidt J, Medne L, Vento J, Chapman KA, Lanpher B, Pearl P, Gropman A, Lourenco C, Bamforth JS, Sharpe C, Pineda M, Schallner J, Bodamer O, Orcesi S, Oberstein SA, Sistermans EA, Yntema HG, Bonnemann C, Waldman AT, et al.

Am J Med Genet A. 2014 Mar;164A(3):627-33. doi: 10.1002/ajmg.a.36309. Epub 2013 Dec 20.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000541611.2

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


This sequence change replaces tyrosine with cysteine at codon 27 of the PTEN protein (p.Tyr27Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo in an individuals affected with PTEN hamartoma tumor syndrome (PHTS) (PMID: 24375884). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on mRNA splicing and protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From ClinGen PTEN Variant Curation Expert Panel, SCV001244234.1

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


PTEN c.80A>G (p.Tyr27Cys) meets criteria to be classified as likely pathogenic 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: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 24375884) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 24375884)

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

Last Updated: Oct 25, 2021

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