NM_002834.5(PTPN11):c.1682C>T (p.Pro561Leu) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Oct 16, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000154538.23

Allele description [Variation Report for NM_002834.5(PTPN11):c.1682C>T (p.Pro561Leu)]

NM_002834.5(PTPN11):c.1682C>T (p.Pro561Leu)

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.1682C>T (p.Pro561Leu)

Other names:

p.P561L:CCG>CTG

HGVS:

NC_000012.12:g.112502226C>T
NG_007459.1:g.88495C>T
NM_001330437.2:c.1694C>T
NM_001374625.1:c.1679C>T
NM_002834.5:c.1682C>TMANE SELECT
NP_001317366.1:p.Pro565Leu
NP_001361554.1:p.Pro560Leu
NP_002825.3:p.Pro561Leu
NP_002825.3:p.Pro561Leu
LRG_614t1:c.1682C>T
LRG_614:g.88495C>T
LRG_614p1:p.Pro561Leu
NC_000012.11:g.112940030C>T
NM_002834.3:c.1682C>T
NM_002834.4:c.1682C>T
NM_080601.1:c.*15593C>T

Protein change:

P560L

Links:

dbSNP: rs141140214

NCBI 1000 Genomes Browser:

rs141140214

Molecular consequence:

NM_001330437.2:c.1694C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.1679C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.1682C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000204210	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Aug 14, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000265846	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 1, 2015)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001467848	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Oct 16, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000204210

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Aug 14, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000265846

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 1, 2015)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001467848

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Oct 16, 2022)

germline

clinical testing

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
not provided	germline	not provided	3	2	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204210.5

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

Description

p.Pro561Leu in exon 14 of PTPN11: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 3 mammals have a leucine (Leu) at this position despite high nearby amin o acid conservation. It has also been identified in 5/66606 of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs141140214).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		3	not provided	2	not provided

From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV000265846.1

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001467848.2

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

Description

Variant summary: PTPN11 c.1682C>T (p.Pro561Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 395798 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database (i.e. in the gnomAD v2.1 and gnomAD v3.1 (non-v2) dataset), including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1682C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. 2 calling it likely benign, while 3 classifying it as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.

#	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: Mar 16, 2025

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