chr12-112489104-C-G

Variant names:

• chr12-112489104-C-G
• rs397507549
• NM_002834.5:c.1528C>G
• PTPN11 p.Gln510Glu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 19 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP2PP3_StrongPP5_Strong

The NM_002834.5(PTPN11):c.1528C>G (p.Gln510Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.57). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000776867: Experimental studies have shown that this missense change affects PTPN11 function (PMID:21803945, 22058153, 23673659, 24935154, 25708222, 26742426)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.Q510K: Pathogenic (ClinVar VariationId 4530410, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.Q510= (synonymous): Likely_benign (ClinVar VariationId 1774623, 2 stars) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 16 samples carry this exact amino acid change out of 64 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Lymphoid Leukemias; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 7.57
• Publications: 84 publications found

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

PTPN11 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124903024 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PTPN11 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 19 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000776867: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 21803945, 22058153, 23673659, 24935154, 25708222, 26742426).; SCV000057458: Published functional studies demonstrate newborn mice with cardiomyocyte-specific overexpression of Q510E develop hypertrophic cardiomyopathy (Schramm et al., 2012);; SCV000698058: Animal model studies concluded that cardiomyocyte-specific expression of Q510E-Shp2 was sufficient to induce the HCM phenotype.; SCV000739999: assays in both in vitro and in vivo models have demonstrated disrupted PTPN11 protein function for p.Q510E, and resultant hypertrophic cardiomyopathy (Ishida H et al. Am. J. Physiol. Heart Circ. Physiol. 2011;301:H1531-9; Schramm C et al. Am. J. Physiol. Heart Circ. Physiol. 2012;302:H231-43; Yu ZH et al. Biochemistry. 2014;53:4136-51; Noda S et al. Biochem. Biophys. Res. Commun. 2016;469:1133-9).; SCV001244986: Functional analysis of cardiomyocyte cell lines demonstrated significant attenuation of myofibrillogenesis and increased proliferation, whilst mice overexpressing this variant showed increased cardiomyocyte size, heart-to-body weight ratios, interventricular septum thickness, cardiomyocyte disarray, thickened ventricular walls and depressed contractile function (Ishida, H., et al. (2011), Schramm, C., et al. (2012)).; SCV000203937: animal models in mice have shown that this variant causes hypertrophic cardiomyopathy (Schramm 2012).; SCV004046160: "In-vitro studies have shown that this missense change abolishes PTPN11 phosphatase activity (PMID: 21803945, 23673659, 24935154, 26742426, 25708222), and mouse models have demonstrated altered cardiac function (PMID: 22058153)."
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 13 pathogenic, 0 benign (OR vs. background: 135.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.Q510K: Pathogenic (ClinVar VariationId 4530410, 1 star); Other variants at the same amino acid residue (not pathogenic): p.Q510= (synonymous): Likely_benign (ClinVar VariationId 1774623, 2 stars)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 4.953). ClinVar shows strong pathogenic missense enrichment: 163 P/LP and 22 B/LB missense entries (ratio 7.4×).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (21/21 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTPN11 NM_002834.5	MANE Select	c.1528C>G p.Gln510Glu	missense	Exon 13 of 16	Prot: NP_002825.3
	PTPN11 NM_001330437.2		c.1540C>G p.Gln514Glu	missense	Exon 13 of 16	Prot: NP_001317366.1 UniProt:
	PTPN11 NM_001374625.1		c.1525C>G p.Gln509Glu	missense	Exon 13 of 16	Prot: NP_001361554.1

PTPN11 NM_002834.5

MANE Select

HGVSc / HGVSpc.1528C>Gp.Gln510Glu

Exon rankExon 13 of 16

missense

Prot: NP_002825.3

PTPN11 NM_001330437.2

HGVSc / HGVSpc.1540C>Gp.Gln514Glu

Exon rankExon 13 of 16

missense

Prot: NP_001317366.1UniProt: Q06124-1

PTPN11 NM_001374625.1

HGVSc / HGVSpc.1525C>Gp.Gln509Glu

Exon rankExon 13 of 16

missense

Prot: NP_001361554.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTPN11 ENST00000351677.7	TSL:1MANE Select	c.1528C>G p.Gln510Glu	missense	Exon 13 of 16	Prot: ENSP00000340944.3 UniProt:
	PTPN11 ENST00000635625.1	TSL:5	c.1540C>G p.Gln514Glu	missense	Exon 13 of 15	Prot: ENSP00000489597.1 UniProt:
	PTPN11 ENST00000635652.1	TSL:3	c.541C>G p.Gln181Glu	missense	Exon 5 of 5	Prot: ENSP00000489541.1 UniProt:

PTPN11 ENST00000351677.7

TSL:1MANE Select

HGVSc / HGVSpc.1528C>Gp.Gln510Glu

Exon rankExon 13 of 16

missense

Prot: ENSP00000340944.3UniProt: Q06124-2

PTPN11 ENST00000635625.1

TSL:5

HGVSc / HGVSpc.1540C>Gp.Gln514Glu

Exon rankExon 13 of 15

missense

Prot: ENSP00000489597.1UniProt: Q06124-1

PTPN11 ENST00000635652.1

TSL:3

HGVSc / HGVSpc.541C>Gp.Gln181Glu

Exon rankExon 5 of 5

missense

Prot: ENSP00000489541.1UniProt: A0A0U1RRI0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Noonan syndrome 1 (5)
3	-	-	RASopathy (3)
2	-	-	PTPN11-related disorder (2)
1	-	-	Autosomal dominant PTPN11-related disorders (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Noonan syndrome 3 (1)
1	-	-	Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines (1)
1	-	-	See cases (1)
-	-	-	LEOPARD syndrome 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
CardioboostCm	Pathogenic	0.99
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
Mutation Taster	N/A	9/91	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.8	H
PhyloP100	Pathogenic	7.6
popEVE	Pathogenic	-5.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.7	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Varity_R	N/A	0.97
VESM-3B	Benign	-15

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs397507549;

hg19: chr12-112926908;

COSMIC: COSV61007076;

COSMIC: COSV61007076;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar