NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jun 1, 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:: RCV000077859.48

Allele description [Variation Report for NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)]

NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)

Gene:

PTPN11:protein tyrosine phosphatase non-receptor type 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.13

Genomic location:

Preferred name:

NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)

Other names:

p.Y279C:TAT>TGT

HGVS:

NC_000012.12:g.112473023A>G
NG_007459.1:g.59292A>G
NM_001330437.2:c.836A>G
NM_001374625.1:c.833A>G
NM_002834.5:c.836A>GMANE SELECT
NM_080601.3:c.836A>G
NP_001317366.1:p.Tyr279Cys
NP_001361554.1:p.Tyr278Cys
NP_002825.3:p.Tyr279Cys
NP_002825.3:p.Tyr279Cys
NP_542168.1:p.Tyr279Cys
LRG_614t1:c.836A>G
LRG_614:g.59292A>G
LRG_614p1:p.Tyr279Cys
NC_000012.11:g.112910827A>G
NM_001330437.1:c.836A>G
NM_002834.3:c.836A>G
NM_002834.4:c.836A>G
NM_080601.1:c.836A>G
NM_080601.2:c.836A>G
Q06124:p.Tyr279Cys
p.Tyr279His

Protein change:

Y278C; TYR279CYS

Links:

UniProtKB: Q06124#VAR_015614; OMIM: 176876.0005; dbSNP: rs121918456

NCBI 1000 Genomes Browser:

rs121918456

Molecular consequence:

NM_001330437.2:c.836A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.833A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.836A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.836A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000057409	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 28, 2022)	germline	clinical testing	Citation Link,
SCV000058294	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Mar 1, 2013)	germline	clinical testing	Citation Link,
SCV000927420	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Oct 3, 2017)	germline	clinical testing	Citation Link,
SCV001246730	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jun 1, 2023)	germline	clinical testing	Citation Link,
SCV001799797	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001955959	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002019548	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002817210	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 30, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000057409.16

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

Description

Published functional studies demonstrate weakened interactions between the N-SH2 and PTP domains leading to sustained RAS-ERK1/2 activation (Yu et al., 2014; Kontaridis et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15121796, 23312806, 26337637, 12161596, 15520399, 16358218, 20308328, 16172598, 16679933, 24820750, 24628801, 16377799, 16638574, 18372317, 18849586, 24037001, 11992261, 24034393, 24775816, 14991917, 24803665, 22822385, 25917897, 26377839, 19768645, 19725129, 28483241, 20493809, 21339643, 23457302, 23673659, 12058348, 19520282, 30732632, 30692697, 30417923, 26918529, 30050098, 31446693, 29907801, 31560489, 31722741, 32164556, 24935154, 24401936, 32866449, 33318624, 31589614, 33258288, 28252636, 9491886, 16053901, 29493581, 33855281)

#	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 Eurofins Ntd Llc (ga), SCV000058294.9

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

From Blueprint Genetics, SCV000927420.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001246730.24

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

PTPN11: PS1, PM1, PM2, PP2, PP3

#	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		3	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001799797.1

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001955959.1

#	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 Revvity Omics, Revvity, SCV002019548.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV002817210.1

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

Description

This variant has been reported to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 30732632, 24820750, 14991917, 33258288). Furthermore, it has been reported in multiple unrelated symptomatic individuals (PMID: 12058348, 12161596, 15520399, 11992261, 16172598, 32164556, 24037001, 24401936, 26918529, 28483241, 30692697, 31560489, 31722741). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 16358218, 16638574, 16377799, 18372317). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

#	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: Sep 16, 2024

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