NM_000314.8(PTEN):c.802-2del AND PTEN hamartoma tumor syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Mar 23, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000335076.11

Allele description [Variation Report for NM_000314.8(PTEN):c.802-2del]

NM_000314.8(PTEN):c.802-2del

Gene:

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

Variant type:

Deletion

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_000314.8(PTEN):c.802-2del

HGVS:

NC_000010.11:g.87960892del
NG_007466.2:g.102454del
NM_000314.8:c.802-2delMANE SELECT
NM_001304717.5:c.1322-2del
NM_001304718.2:c.211-2del
LRG_311t1:c.802-2del
LRG_311:g.102454del
NC_000010.10:g.89720649del
NC_000010.10:g.89720649del
NC_000010.10:g.89720649delA
NM_000314.4:c.802-2delA
NM_000314.7(PTEN):c.802-2del

Links:

dbSNP: rs886047397

NCBI 1000 Genomes Browser:

rs886047397

Molecular consequence:

NM_000314.8:c.802-2del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001304717.5:c.1322-2del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001304718.2:c.211-2del - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: PTEN hamartoma tumor syndrome (PHTS)
Synonyms:: PTEN Hamartomatous Tumour Syndrome
Identifiers:: MONDO: MONDO:0017623; MeSH: D006223; MedGen: C1959582

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Homeodomain-like superfamily protein [Arabidopsis thaliana]
Homeodomain-like superfamily protein [Arabidopsis thaliana]
gi|15218361|ref|NP_175020.1|

Protein
Polr2a RNA polymerase II subunit A [Rattus norvegicus]
Polr2a RNA polymerase II subunit A [Rattus norvegicus]
Gene ID:363633

Gene
363633[uid] AND (alive[prop]) (1)
Gene
PHACADRAFT_264340 [Phanerochaete carnosa HHB-10118-sp]
PHACADRAFT_264340 [Phanerochaete carnosa HHB-10118-sp]
Gene ID:18918791

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000365740	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV000766802	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 12, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 9467011, 21194675, 28492532
SCV001335275	Clingen PTEN Variant Curation Expert Panel, Clingen	reviewed by expert panel (ClinGen PTEN ACMG Specifications v2)	Likely pathogenic (Mar 23, 2020)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000365740

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

Citation Link,

SCV000766802

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 12, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001335275

Clingen PTEN Variant Curation Expert Panel, Clingen

reviewed by expert panel

(ClinGen PTEN ACMG Specifications v2)

Likely pathogenic
(Mar 23, 2020)

germline

curation

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, curation

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.

Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, Liaw D, Caron S, Duboué B, Lin AY, Richardson AL, Bonnetblanc JM, Bressieux JM, Cabarrot-Moreau A, Chompret A, Demange L, Eeles RA, Yahanda AM, Fearon ER, Fricker JP, Gorlin RJ, Hodgson SV, et al.

Hum Mol Genet. 1998 Mar;7(3):507-15.

PubMed [citation]

PMID:: 9467011

See all PubMed Citations (4)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000365740.3

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

Description

The PTEN c.802-2delA variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. This variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Based on the potential impact of splice acceptor variants and the lack of clarifying evidence, the c.802-2delA variant is classified as a variant of unknown significance but suspicious for pathogenicity for PTEN hamartoma tumor syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000766802.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 301423). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 7 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675).

#	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 Clingen PTEN Variant Curation Expert Panel, Clingen, SCV001335275.1

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

Description

PTEN c.802-2del (IVS7-2del) 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). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5' to c.1121 (NM_000314.4). PM2: Absent in large sequenced populations

#	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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