12-112450394-G-T

Variant names:

• chr12-112450394-G-T
• rs121918453
• NM_002834.5:c.214G>T
• PTPN11 p.Ala72Ser

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 14 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_StrongO3_ModerateO4_SupportingO5_SupportingO6_SupportingO7_StrongO8_Supporting

The NM_002834.5(PTPN11):c.214G>T (p.Ala72Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The gene PTPN11 is a tumor suppressor gene (CancerMine: 27 TSG, 73 oncogene, 18 driver citations). The gene PTPN11 is a known oncogene (CancerMine: 27 TSG, 73 oncogene, 18 driver citations). The gene PTPN11 is a cancer driver gene (CancerMine: 27 TSG, 73 oncogene, 18 driver citations). The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0000009, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. 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: 9.99). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002540265: "In vitro functional studies demonstrated that the p.Ala72Ser variant significantly increased PTPN11 phosphatase activity and prolonged ERK activation." PMID:15179047" 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.A72G: Pathogenic/Likely_pathogenic (ClinVar VariationId 13325, 2 stars) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 25 samples carry this exact amino acid change out of 150 samples with a variant at this residue. The variant has been observed in cBioPortal in 10 samples across 8 studies and 6 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Noonan syndrome 1 (ns1); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 9.99
• Publications: 7 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

Classification according to ACGS-UK Somatic Oncogenicity v2025

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 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		CGI exact DNA-change oncogenic — Strong (O1); TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (4.0 pts): CGI (Cancer Genome Interpreter), ClinVar germline P/LP in TSG (★★)
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000001, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=10 | studies=8 | cancer types=6 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: true | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Strong hotspot (cancerhotspots.org): >50 total samples, ≥10 same AA change; Note: exclude MSK/TCGA-derived samples from cancerhotspots count to avoid double-counting with O4; cancerhotspots.org: total samples at AA position = 150, same AA change = 25; Exclude MSK/TCGA-derived samples from count to avoid double-counting with O4; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 24 pathogenic, 0 benign (OR vs. background: 245.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 4.95 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

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.214G>T p.Ala72Ser	missense	Exon 3 of 16	Prot: NP_002825.3
	PTPN11 NM_001330437.2		c.214G>T p.Ala72Ser	missense	Exon 3 of 16	Prot: NP_001317366.1 UniProt:
	PTPN11 NM_001374625.1		c.211G>T p.Ala71Ser	missense	Exon 3 of 16	Prot: NP_001361554.1

PTPN11 NM_002834.5

MANE Select

HGVSc / HGVSpc.214G>Tp.Ala72Ser

Exon rankExon 3 of 16

missense

Prot: NP_002825.3

PTPN11 NM_001330437.2

HGVSc / HGVSpc.214G>Tp.Ala72Ser

Exon rankExon 3 of 16

missense

Prot: NP_001317366.1UniProt: Q06124-1

PTPN11 NM_001374625.1

HGVSc / HGVSpc.211G>Tp.Ala71Ser

Exon rankExon 3 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.214G>T p.Ala72Ser	missense	Exon 3 of 16	Prot: ENSP00000340944.3 UniProt:
	PTPN11 ENST00000635625.1	TSL:5	c.214G>T p.Ala72Ser	missense	Exon 3 of 15	Prot: ENSP00000489597.1 UniProt:
	PTPN11 ENST00000392597.5	TSL:1	c.214G>T p.Ala72Ser	missense	Exon 3 of 11	Prot: ENSP00000376376.1 UniProt:

PTPN11 ENST00000351677.7

TSL:1MANE Select

HGVSc / HGVSpc.214G>Tp.Ala72Ser

Exon rankExon 3 of 16

missense

Prot: ENSP00000340944.3UniProt: Q06124-2

PTPN11 ENST00000635625.1

TSL:5

HGVSc / HGVSpc.214G>Tp.Ala72Ser

Exon rankExon 3 of 15

missense

Prot: ENSP00000489597.1UniProt: Q06124-1

PTPN11 ENST00000392597.5

TSL:1

HGVSc / HGVSpc.214G>Tp.Ala72Ser

Exon rankExon 3 of 11

missense

Prot: ENSP00000376376.1UniProt: Q06124-3

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome Warning	AF: 6.84e-7	AC:1	Hom:0	AN:1461322	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000491	AC:1	Hom:0	AN:203630	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
3	-	-	Noonan syndrome 1 (3)
3	-	-	RASopathy (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
1	-	-	LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
1	-	-	Noonan syndrome (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
CardioboostCm	Uncertain	0.57
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-8.4
GPN-Star score	N/A	8.4
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.96	D
Mutation Taster	N/A	2/98	disease causing (ClinVar)
MutationAssessor	Benign	0.66	N
PhyloP100	Pathogenic	10
popEVE	Benign	-3.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.081	T
Varity_R	N/A	0.93
VESM-3B	Benign	-5.3

Showing 30 of 30 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: rs121918453;

hg19: chr12-112888198;

COSMIC: COSV61004869;

COSMIC: COSV61004869;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar