NM_000314.8(PTEN):c.737C>T (p.Pro246Leu) AND Cowden syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Apr 5, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000660237.5

Allele description [Variation Report for NM_000314.8(PTEN):c.737C>T (p.Pro246Leu)]

NM_000314.8(PTEN):c.737C>T (p.Pro246Leu)

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.737C>T (p.Pro246Leu)

Other names:

p.P246L:CCG>CTG; NM_000314.6(PTEN):c.737C>T(p.Pro246Leu)

HGVS:

NC_000010.11:g.87957955C>T
NG_007466.2:g.99517C>T
NM_000314.8:c.737C>TMANE SELECT
NM_001304717.5:c.1256C>T
NM_001304718.2:c.146C>T
NP_000305.3:p.Pro246Leu
NP_001291646.4:p.Pro419Leu
NP_001291647.1:p.Pro49Leu
LRG_311t1:c.737C>T
LRG_311:g.99517C>T
NC_000010.10:g.89717712C>T
NM_000314.4:c.737C>T
NM_000314.5:c.737C>T
NM_000314.6:c.737C>T
P60484:p.Pro246Leu
p.P246L

Protein change:

P246L

Links:

UniProtKB: P60484#VAR_008740; dbSNP: rs587782350

NCBI 1000 Genomes Browser:

rs587782350

Molecular consequence:

NM_000314.8:c.737C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001304717.5:c.1256C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001304718.2:c.146C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cowden syndrome 1 (CWS1)
Identifiers:: MONDO: MONDO:0008021; MedGen: CN072330; OMIM: 158350

Recent activity

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Human DNA sequence from clone CH502-231H22 on chromosome 6, complete sequence
Human DNA sequence from clone CH502-231H22 on chromosome 6, complete sequence
gi|20338566|emb|AL713890.7|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000782243	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000786146	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Mar 7, 2018)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17942903, 22261759, 10400993, 26681312, 14566704, 24375884, 21828076, 27477328 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV000840053	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 3, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001469124	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Feb 5, 2020)	germline	clinical testing
SCV004019958	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Apr 5, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29785012, 32350270 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

In vivo functional analysis of the counterbalance of hyperactive phosphatidylinositol 3-kinase p110 catalytic oncoproteins by the tumor suppressor PTEN.

Andrés-Pons A, Rodríguez-Escudero I, Gil A, Blanco A, Vega A, Molina M, Pulido R, Cid VJ.

Cancer Res. 2007 Oct 15;67(20):9731-9.

PubMed [citation]

PMID:: 17942903

Elevated plasma succinate in PTEN, SDHB, and SDHD mutation-positive individuals.

Hobert JA, Mester JL, Moline J, Eng C.

Genet Med. 2012 Jun;14(6):616-9. doi: 10.1038/gim.2011.63. Epub 2012 Jan 26.

PubMed [citation]

PMID:: 22261759
PMCID:: PMC4019996

See all PubMed Citations (11)

Details of each submission

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782243.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000786146.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840053.1

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

Description

This c.737C>T (p.Pro246Leu) variant was detected in 3 members of a family with Bannayan-Riley-Ruvalcaba syndrome (BRRS) [PMID 10400993]. BRRS is allelic to Cowden syndrome and is characterized by macrocephaly, hamartomatous intestinal polyposis, lipomas, and pigmented macules of the glans penis. The variant was further detected de novo in a cohort of 264 trio diagnosed with seizure. The patient had infantile spasms in addition to vascular anomalies and macrocephaly [PMID 23934111]. We have observed this variant, de novo, in a patient with autism in our internal database. This c.737C>T (p.Pro246Leu) variant was not observed in the gnomAD population database. Proline at amino acid position 246 is conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Pro246Leu to be deleterious. This variant is thus classified as pathogenic.

#	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 Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001469124.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004019958.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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, 32350270].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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