VCV000007825.9 - ClinVar

NM_000314.8(PTEN):c.104T>G (p.Met35Arg)

Germline

Top reviewed classifications are shown here.

Submission summary:

4 submissions

4 submitters

2 conditions

Reviewed by expert panel

Pathogenic

Jul 2018 by Clingen PTEN V… FDA Recognized Database

for PTEN hamartoma tumor syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000314.8(PTEN):c.104T>G (p.Met35Arg)

Variation ID: 7825 Accession: VCV000007825.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.31 10: 87894049 (GRCh38) [ NCBI UCSC ] 10: 89653806 (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	Jun 30, 2018	Feb 14, 2024	Jul 25, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_000314.8:c.104T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000305.3:p.Met35Arg	missense
NM_001304717.5:c.623T>G	NP_001291646.4:p.Met208Arg	missense
NM_001304718.2:c.-602T>G		5 prime UTR
NC_000010.11:g.87894049T>G
NC_000010.10:g.89653806T>G
NG_007466.2:g.35611T>G
LRG_311:g.35611T>G
	P60484:p.Met35Arg

... more HGVS ... less HGVS

Protein change

M35R, M208R

Other names

NM_000314.6(PTEN):c.104T>G

Canonical SPDI

NC_000010.11:87894048:T:G

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

ClinGen: CA000268 UniProtKB: P60484#VAR_008036 OMIM: 601728.0011 dbSNP: rs121909225 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	3106	3616

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	Likely pathogenic (2)	criteria provided, single submitter	Nov 6, 2023	RCV000008271.5
PTEN hamartoma tumor syndrome	Pathogenic (2)	reviewed by expert panel	Jul 25, 2018	RCV000790896.8

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 (Jul 25, 2018)	reviewed by expert panel (ClinGen PTEN ACMG Specifications v1) Method: curation	PTEN hamartoma tumor syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Clingen PTEN Variant Curation Expert Panel, Clingen FDA Recognized Database Accession: SCV000930136.1 First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019	Publications: PubMed (4) PubMed: 25875300‚ 21828076‚ 9425889‚ 27535533 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2374c339-e2d7-4496-9d9a-d33c1abd8dce Comment: PTEN c.104T>G (p.Met35Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID … (more) PTEN c.104T>G (p.Met35Arg) meets criteria to be classified as 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (PMID 9425889) PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300) PM2: Absent in large sequenced populations (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. (less)
Pathogenic (Jan 09, 2024)	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: SCV001580433.3 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 9425889‚ 21828076‚ 25875300‚ 17526801‚ 26468640 Comment: This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 35 of the PTEN protein (p.Met35Arg). … (more) This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 35 of the PTEN protein (p.Met35Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 9425889). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7825). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 21828076, 25875300). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Met35 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 17526801, 26468640; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Nov 06, 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: SCV004189539.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Publications: PubMed (3) PubMed: 29785012‚ 37819013‚ 9425889 Comment: This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function … (more) This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29785012]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 37819013, 9425889]. (less)
Pathogenic (Sep 01, 2003)	no assertion criteria provided Method: literature only	COWDEN SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028478.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 30, 2018	Publications: PubMed (4) PubMed: 9425889‚ 12938083‚ 8673088‚ 11875759 Comment on evidence: In a patient who was considered to have juvenile polyposis coli, Olschwang et al. (1998) identified a T-to-G transversion in exon 2 predicted to substitute … (more) In a patient who was considered to have juvenile polyposis coli, Olschwang et al. (1998) identified a T-to-G transversion in exon 2 predicted to substitute an arginine for the methionine at codon 35. The PTEN protein demonstrates exceedingly high phylogenic conservation, with the human protein identical to that of dog and differing from that of mouse by a single amino acid change at codon 398. Codon 35 occurs in the region of PTEN that presents significant homology with tensin (600076) and auxilin. Taken together, these observations suggested that the DNA variation in this patient was deleterious. The patient underwent gastroscopy and colonoscopy at 7 years of age, after a 3-year history of intermittent rectal bleeding. Juvenile polyps were found throughout the stomach, duodenum, and colon. At the age of 10 years, clinical evaluations had not revealed any extra-digestive manifestations that could be associated with Cowden disease. Both parents underwent colonoscopy that showed normal digestive tracts. The genotypes at 8 highly polymorphic microsatellite loci in the parents and patient confirmed mendelian inheritance. Sequencing of exon 2 amplified from the DNAs of both parents revealed only codon 35 for methionine, demonstrating that codon 35 of arginine was a new mutation. Eng and Peacocke (1998) pointed out that the penetrance of Cowden syndrome (CWS1; 158350) is well under 10% below 15 years of age (Nelen et al., 1996); thus children with JPS, according to diagnostic criteria, may develop other features of Cowden syndrome as they age. Waite and Eng (2002) supported this conclusion and stated that juvenile intestinal polyposis is not a so-called PTEN hamartoma-tumor syndrome (PHTS). They suggested that the discovery of the germline PTEN mutation in an individual considered to have JPS should raise a suspicion that the clinical diagnosis is incorrect and that such an individual should be managed medically in the same manner as all patients with PHTS. (less)

Comment:

PTEN c.104T>G (p.Met35Arg) meets criteria to be classified as 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (PMID 9425889) PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300) PM2: Absent in large sequenced populations (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.

Comment:

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 35 of the PTEN protein (p.Met35Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 9425889). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7825). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 21828076, 25875300). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Met35 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 17526801, 26468640; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29785012]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 37819013, 9425889].

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
Identification of c.104T>G, p.Met35Arg (NM_00314.8) heterozygous variant in exon 2 of PTEN as the causative factor for Cowden syndrome: a medical case study.	Mansilla-Polo M	Clinical and experimental dermatology	2024	PMID: 37819013
Multiplex assessment of protein variant abundance by massively parallel sequencing.	Matreyek KA	Nature genetics	2018	PMID: 29785012
Analysis of protein-coding genetic variation in 60,706 humans.	Lek M	Nature	2016	PMID: 27535533
Breast Cancer and Non-Hodgkin Lymphoma in a Young Male with Cowden Syndrome.	Hagelstrom RT	Pediatric blood & cancer	2016	PMID: 26468640
A functional dissection of PTEN N-terminus: implications in PTEN subcellular targeting and tumor suppressor activity.	Gil A	PloS one	2015	PMID: 25875300
A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.	Rodríguez-Escudero I	Human molecular genetics	2011	PMID: 21828076
The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management.	Tan WH	Journal of medical genetics	2007	PMID: 17526801
PTEN: one gene, many syndromes.	Eng C	Human mutation	2003	PMID: 12938083
Protean PTEN: form and function.	Waite KA	American journal of human genetics	2002	PMID: 11875759
PTEN germ-line mutations in juvenile polyposis coli.	Olschwang S	Nature genetics	1998	PMID: 9425889
Localization of the gene for Cowden disease to chromosome 10q22-23.	Nelen MR	Nature genetics	1996	PMID: 8673088
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2374c339-e2d7-4496-9d9a-d33c1abd8dce	-	-	-	-
click to load more click to collapse

Text-mined citations for rs121909225 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000314.8(PTEN):c.104T>G (p.Met35Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121909225 ...