NM_002834.5(PTPN11):c.1678C>T (p.Leu560Phe) AND RASopathy

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Sep 17, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000159057.15

Allele description [Variation Report for NM_002834.5(PTPN11):c.1678C>T (p.Leu560Phe)]

NM_002834.5(PTPN11):c.1678C>T (p.Leu560Phe)

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.1678C>T (p.Leu560Phe)

Other names:

p.L560F:CTC>TTC; NM_002834.4(PTPN11):c.1678C>T

HGVS:

NC_000012.12:g.112502222C>T
NG_007459.1:g.88491C>T
NM_001330437.2:c.1690C>T
NM_001374625.1:c.1675C>T
NM_002834.5:c.1678C>TMANE SELECT
NP_001317366.1:p.Leu564Phe
NP_001361554.1:p.Leu559Phe
NP_002825.3:p.Leu560Phe
LRG_614t1:c.1678C>T
LRG_614:g.88491C>T
NC_000012.11:g.112940026C>T
NM_002834.3:c.1678C>T
NM_002834.4:c.1678C>T
c.1678C>T

Protein change:

L559F

Links:

dbSNP: rs397516797

Molecular consequence:

NM_001330437.2:c.1690C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.1675C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.1678C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000208999	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Feb 20, 2019)	germline	clinical testing	Citation Link,
SCV000616409	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications PTPN11 V2.1.0)	Likely Benign (Sep 17, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000815176	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 15, 2026)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12960218, 15987685, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000208999

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Feb 20, 2019)

germline

clinical testing

Citation Link,

SCV000616409

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications PTPN11 V2.1.0)

Likely Benign
(Sep 17, 2024)

germline

curation

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

Citation Link,

SCV000815176

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 15, 2026)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes.

Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, Fazio VM, Di Ciommo V, Marino B, Pizzuti A, Dallapiccola B.

J Med Genet. 2003 Sep;40(9):704-8. No abstract available.

PubMed [citation]

PMID:: 12960218
PMCID:: PMC1735592

Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes.

Keilhack H, David FS, McGregor M, Cantley LC, Neel BG.

J Biol Chem. 2005 Sep 2;280(35):30984-93. Epub 2005 Jun 29.

PubMed [citation]

PMID:: 15987685

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000208999.3

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 ClinGen RASopathy Variant Curation Expert Panel, SCV000616409.5

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

Description

The c.1678C>T (p.Leu560Phe) variant in PTPN11 (NM_002834.5(PTPN11):c.1678C>T (p.Leu560Phe)) has been identified in individuals with some features of a RASopathy but none were diagnosed with a RASopathy (PS4 not met; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data; GTR ID's: 28338, 26957, 21766; SCV000061285.5; SCV000208999.2; SCV000207690.1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data: GTR ID: 26957; SCV000208999.2). In vitro functional studies provide some evidence that the p.Leu560Phe variant does not impact protein function (BS3; PMID: 15987685). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied: BS3, BP5 (Version 2.1; 09/17/2024).

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000815176.7

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 560 of the PTPN11 protein (p.Leu560Phe). This variant is present in population databases (rs397516797, gnomAD 0.01%). This missense change has been observed in individual(s) with Noonan syndrome and congenital hypertrophic cardiomyopathy (PMID: 12960218). ClinVar contains an entry for this variant (Variation ID: 44599). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. Experimental studies have shown that this missense change does not substantially affect PTPN11 function (PMID: 15987685). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Aug 16, 2026

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