VCV002630888.4 - ClinVar

NM_000314.8(PTEN):c.655C>T (p.Gln219Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely oncogenic

criteria provided, single submitter

Variant Details

Identifiers

NM_000314.8(PTEN):c.655C>T (p.Gln219Ter)

Variation ID: 2630888 Accession: VCV002630888.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.31 10: 87957873 (GRCh38) [ NCBI UCSC ] 10: 89717630 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 20, 2023	Feb 14, 2024	Sep 29, 2023
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000314.8:c.655C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000305.3:p.Gln219Ter	nonsense
NM_001304717.5:c.1174C>T	NP_001291646.4:p.Gln392Ter	nonsense
NM_001304718.2:c.64C>T	NP_001291647.1:p.Gln22Ter	nonsense
NC_000010.11:g.87957873C>T
NC_000010.10:g.89717630C>T
NG_007466.2:g.99435C>T
LRG_311:g.99435C>T
LRG_311t1:c.655C>T	LRG_311p1:p.Gln219Ter

... more HGVS ... less HGVS

Protein change

Q219*, Q22*, Q392*

Other names

Canonical SPDI

NC_000010.11:87957872:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PTEN		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	3102	3612

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cowden syndrome 1	Pathogenic (1)	criteria provided, single submitter	Sep 29, 2023	RCV003455815.1
PTEN hamartoma tumor syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2022	RCV003509818.2
PTEN-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 18, 2023	RCV004531535.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PTEN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004103607.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The PTEN c.655C>T variant is predicted to result in premature protein termination (p.Gln219). This variant has been reported in individuals with PTEN hamartoma tumor syndrome … (more) The PTEN c.655C>T variant is predicted to result in premature protein termination (p.Gln219). This variant has been reported in individuals with PTEN hamartoma tumor syndrome (Figure 7, Cho et al. 2008. PubMed ID: 18594467; Figure S1, Ngeow et al. 2011. PubMed ID: 21956414; Table 2, Ngeow et al. 2014. PubMed ID: 24778394; Figure 3, Kobayashi et al. 2020. PubMed ID: 32461083; Table S1, Pena-Couso et al. 2022. PubMed ID: 35227301). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Sep 29, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Cowden syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004188836.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Oct 31, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	PTEN hamartoma tumor syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004295316.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 18594467‚ 32461083‚ 9467011‚ 21194675 Comment: This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict … (more) This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This premature translational stop signal has been observed in individual(s) with Cowden syndrome (PMID: 18594467, 32461083). This sequence change creates a premature translational stop signal (p.Gln219*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). (less)

Comment:

The PTEN c.655C>T variant is predicted to result in premature protein termination (p.Gln219*). This variant has been reported in individuals with PTEN hamartoma tumor syndrome (Figure 7, Cho et al. 2008. PubMed ID: 18594467; Figure S1, Ngeow et al. 2011. PubMed ID: 21956414; Table 2, Ngeow et al. 2014. PubMed ID: 24778394; Figure 3, Kobayashi et al. 2020. PubMed ID: 32461083; Table S1, Pena-Couso et al. 2022. PubMed ID: 35227301). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This premature translational stop signal has been observed in individual(s) with Cowden syndrome (PMID: 18594467, 32461083). This sequence change creates a premature translational stop signal (p.Gln219*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Cowden syndrome complicated by schizophrenia: A first clinical report.	Kobayashi Y	European journal of medical genetics	2020	PMID: 32461083
A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands.	Tan MH	American journal of human genetics	2011	PMID: 21194675
First report of ovarian dysgerminoma in Cowden syndrome with germline PTEN mutation and PTEN-related 10q loss of tumor heterozygosity.	Cho MY	The American journal of surgical pathology	2008	PMID: 18594467
Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.	Marsh DJ	Human molecular genetics	1998	PMID: 9467011

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Likely oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004673881.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity classification for each SCV record. (Last evaluated)	Review Status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Tumor type Help The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Likely oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094214.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000314.8(PTEN):c.655C>T (p.Gln219Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for this variant ...