12-112450394-G-C

Variant names:

• chr12-112450394-G-C
• rs121918453
• NM_002834.5:c.214G>C
• PTPN11 p.Ala72Pro

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 17 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP2PP3_ModeratePP5_Strong

The NM_002834.5(PTPN11):c.214G>C (p.Ala72Pro) 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: 9.99). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000698069: The variant was absent in 251056 control chromosomes. c.214G>C has been reported in the literature in individuals affected with Noonan Syndrome (example, PMID:18759865, 26918529). At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID:16358218). The most pronounced variant effect results in statistically significant higher phosphatase activities basally and after stimulation with BTAM peptide consistent with a gain of function mechanism of disease.". 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) A different missense variant at the same amino acid position has been reported as oncogenic in ClinVar. The variant position is a cancer hotspot (cancerhotspots.org) with 150 samples affected at this amino acid position. 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)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.99
• Publications: 122 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 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 17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000698069: The variant was absent in 251056 control chromosomes. c.214G>C has been reported in the literature in individuals affected with Noonan Syndrome (example, PMID: 18759865, 26918529). At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 16358218). The most pronounced variant effect results in statistically significant higher phosphatase activities basally and after stimulation with BTAM peptide consistent with a gain of function mechanism of disease.
	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: 24 pathogenic, 0 benign (OR vs. background: 245.0).
	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.A72G: Pathogenic/Likely_pathogenic (ClinVar VariationId 13325, 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 — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 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.214G>C p.Ala72Pro	missense	Exon 3 of 16	Prot: NP_002825.3
	PTPN11 NM_001330437.2		c.214G>C p.Ala72Pro	missense	Exon 3 of 16	Prot: NP_001317366.1 UniProt:
	PTPN11 NM_001374625.1		c.211G>C p.Ala71Pro	missense	Exon 3 of 16	Prot: NP_001361554.1

PTPN11 NM_002834.5

MANE Select

HGVSc / HGVSpc.214G>Cp.Ala72Pro

Exon rankExon 3 of 16

missense

Prot: NP_002825.3

PTPN11 NM_001330437.2

HGVSc / HGVSpc.214G>Cp.Ala72Pro

Exon rankExon 3 of 16

missense

Prot: NP_001317366.1UniProt: Q06124-1

PTPN11 NM_001374625.1

HGVSc / HGVSpc.211G>Cp.Ala71Pro

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>C p.Ala72Pro	missense	Exon 3 of 16	Prot: ENSP00000340944.3 UniProt:
	PTPN11 ENST00000635625.1	TSL:5	c.214G>C p.Ala72Pro	missense	Exon 3 of 15	Prot: ENSP00000489597.1 UniProt:
	PTPN11 ENST00000392597.5	TSL:1	c.214G>C p.Ala72Pro	missense	Exon 3 of 11	Prot: ENSP00000376376.1 UniProt:

PTPN11 ENST00000351677.7

TSL:1MANE Select

HGVSc / HGVSpc.214G>Cp.Ala72Pro

Exon rankExon 3 of 16

missense

Prot: ENSP00000340944.3UniProt: Q06124-2

PTPN11 ENST00000635625.1

TSL:5

HGVSc / HGVSpc.214G>Cp.Ala72Pro

Exon rankExon 3 of 15

missense

Prot: ENSP00000489597.1UniProt: Q06124-1

PTPN11 ENST00000392597.5

TSL:1

HGVSc / HGVSpc.214G>Cp.Ala72Pro

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Autosomal dominant PTPN11-related disorders (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Noonan syndrome (1)
1	-	-	Noonan syndrome with multiple lentigines (1)
1	-	-	RASopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	31
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
CardioboostCm	Pathogenic	0.96
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.97
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.79	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Benign	0.48	N
PhyloP100	Pathogenic	10
popEVE	Benign	-3.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.10	T
Varity_R	N/A	0.98
VESM-3B	Benign	-7.4

Showing 29 of 29 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: COSV61006317;

COSMIC: COSV61006317;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar