rs397507547

Variant names:

• chr12-112489086-A-G
• rs397507547
• NM_002834.5:c.1510A>G
• PTPN11 p.Met504Val

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 23 classification points (ACMG Germline Pathogenicity v2019): 23P and 0B. PS3PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.1510A>G (p.Met504Val) 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: 8.95). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000253877: Experimental studies have shown that this missense change affects PTPN11 function (PMID:16358218)." 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.M504T: Likely_pathogenic (ClinVar VariationId 4819800, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M504I: Uncertain_significance (ClinVar VariationId 4808314, 1 star) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 9 samples carry this exact amino acid change out of 18 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:40
• Conservation: PhyloP100: 8.95
• Publications: 54 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• Noonan syndrome

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

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

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

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

Our verdict: Pathogenic. The variant received 23 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000253877: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16358218).; SCV000698057: The mutation lies within a region of the gene coding for the highly conserved PTP domain of the protein tyrosine phosphatase 11 and was shown to increase the phosphatase activity in functional studies.; SCV000057454: Published functional studies demonstrate a damaging effect, resulting in increased phosphatase activity (Niihori et al., 2005);; SCV000206705: Functional analyses of the p.Met504Val protein show increased catalytic activity upon growth factor-mediated stimulation (Niihori 2005, Tartaglia 2006), consistent with the established disease mechanisms of Noonan syndrome. References: Niihori T et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. 2005 J Hum Genet. 50(4):192-202. PMID: 15834506. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 78(2): 279-290. PMID: 16358218.; SCV000061278: "In vitro functional studies provide some evidence that the p.Met504Val variant may impact protein function and reduce phosphatase activity." PMID:15834506, PMID:16358218; SCV000616376: "In vitro functional studies provide some evidence that the p.Met504Val variant may impact protein function (PS3; PMID: 15834506)."; SCV000996118: Functional characterization of the p.Met504Val demonstrated altered PTPN11 phosphatase activity compared to wild-type protein (PMID: 16358218).; SCV002012209: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15834506).; SCV002556631: "This variant is located within the highly conserved PTP domain of the protein and functional studies show altered (increased) phosphatase activity compared with WT protein." PMID:15834506; SCV002767130: Functional analysis using mammalian cell lines showed a 3-fold increase in phosphatase activity in p.(Met504Val) mutant cells relative to wild-type (PMID: 15834506); SCV003920362: "In vitro functional studies support that this variant will impact the protein by causing an increase in phosphatase activity (Niihori 2005 PMID15834506)."; SCV001190461: "In vitro functional studies support that this variant will impact the protein by causing an increase in phosphatase activity (Niihori 2005 PMID15834506)."; SCV002705011: "In vitro analysis of this alteration demonstrated mild phosphatase activation, a three-fold increased compared to wildtype (Niihori, 2005)."; SCV004115089: Functional studies demonstrate increased phosphatase activity, consistent with a gain-of-function mechanism (Niihori et al. 2005. PubMed ID: 15834506; Tartaglia et al. 2006. PubMed ID: 16358218).
• PM1: 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: 24 pathogenic, 0 benign (OR vs. background: 245.0).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
• PM5: 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.M504T: Likely_pathogenic (ClinVar VariationId 4819800, 1 star); Other variants at the same amino acid residue (not pathogenic): p.M504I: Uncertain_significance (ClinVar VariationId 4808314, 1 star)
• PP2: 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: 164 P/LP and 22 B/LB missense entries (ratio 7.5×).
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
• PP5: ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s).

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.1510A>G	p.Met504Val	missense	Exon 13 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.1522A>G	p.Met508Val	missense	Exon 13 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.1507A>G	p.Met503Val	missense	Exon 13 of 16	NP_001361554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.1510A>G	p.Met504Val	missense	Exon 13 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.1522A>G	p.Met508Val	missense	Exon 13 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000635652.1	TSL:3	c.523A>G	p.Met175Val	missense	Exon 5 of 5	ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251490 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
16	-	-	Noonan syndrome 1 (16)
12	-	-	not provided (12)
3	-	-	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (3)
3	-	-	RASopathy (3)
2	-	-	Noonan syndrome (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Male infertility with azoospermia or oligozoospermia due to single gene mutation (1)
1	-	-	Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
1	-	-	PTPN11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.98
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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.

Other links and lift over

dbSNP: rs397507547;

hg19: chr12-112926890;

COSMIC: COSV61012722;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar