12-112489104-C-T

Variant names:

• chr12-112489104-C-T
• rs397507549
• NM_002834.5:c.1528C>T
• PTPN11 p.Gln510*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2

The NM_002834.5(PTPN11):c.1528C>T (p.Gln510*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) 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). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The variant position is a cancer hotspot (cancerhotspots.org) with 64 samples affected at this amino acid position. This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Metachondromatosis (metcds); it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 63 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 10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 13 of 16) at amino acid 510 of 593, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	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.

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>T p.Gln510*	stop_gained	Exon 13 of 16	Prot: NP_002825.3
	PTPN11 NM_001330437.2		c.1540C>T p.Gln514*	stop_gained	Exon 13 of 16	Prot: NP_001317366.1 UniProt:
	PTPN11 NM_001374625.1		c.1525C>T p.Gln509*	stop_gained	Exon 13 of 16	Prot: NP_001361554.1

PTPN11 NM_002834.5

MANE Select

HGVSc / HGVSpc.1528C>Tp.Gln510*

Exon rankExon 13 of 16

stop_gained

Prot: NP_002825.3

PTPN11 NM_001330437.2

HGVSc / HGVSpc.1540C>Tp.Gln514*

Exon rankExon 13 of 16

stop_gained

Prot: NP_001317366.1UniProt: Q06124-1

PTPN11 NM_001374625.1

HGVSc / HGVSpc.1525C>Tp.Gln509*

Exon rankExon 13 of 16

stop_gained

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>T p.Gln510*	stop_gained	Exon 13 of 16	Prot: ENSP00000340944.3 UniProt:
	PTPN11 ENST00000635625.1	TSL:5	c.1540C>T p.Gln514*	stop_gained	Exon 13 of 15	Prot: ENSP00000489597.1 UniProt:
	PTPN11 ENST00000635652.1	TSL:3	c.541C>T p.Gln181*	stop_gained	Exon 5 of 5	Prot: ENSP00000489541.1 UniProt:

PTPN11 ENST00000351677.7

TSL:1MANE Select

HGVSc / HGVSpc.1528C>Tp.Gln510*

Exon rankExon 13 of 16

stop_gained

Prot: ENSP00000340944.3UniProt: Q06124-2

PTPN11 ENST00000635625.1

TSL:5

HGVSc / HGVSpc.1540C>Tp.Gln514*

Exon rankExon 13 of 15

stop_gained

Prot: ENSP00000489597.1UniProt: Q06124-1

PTPN11 ENST00000635652.1

TSL:3

HGVSc / HGVSpc.541C>Tp.Gln181*

Exon rankExon 5 of 5

stop_gained

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

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	39
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
Mutation Taster	N/A	7/193	disease causing (fs/PTC)
PhyloP100	Pathogenic	7.6
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 14 of 14 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.010	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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar