Variant classification summary

NM_001330437.1:c.1522A>G

PTPN11 · NP_001317366.1:p.(Met508Val) · NM_001330437.1

GRCh37: chr12:112926890 A>G · GRCh38: chr12:112489086 A>G

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Likely Pathogenic

PS3 supporting PS4 strong PP2 supporting PP3 supporting PP5 supporting

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Met508Val)

gnomAD AF

1.239033009078395e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001330437.1:c.1522A>G (p.Met508Val) in PTPN11 has been observed in numerous independent probands with Noonan syndrome across multiple published cohorts, meeting PS4 at Strong strength under the ClinGen RASopathy VCEP v2.3.0 framework.

2

Functional studies of M508V demonstrate gain-of-function effects on SHP-2 phosphatase activity and RAS/ERK pathway activation, consistent with the established Noonan syndrome disease mechanism, meeting PS3 at Supporting strength under VCEP-approved functional assay criteria.

3

The REVEL in silico score of 0.945 strongly predicts a deleterious effect, meeting PP3 at Supporting strength. PTPN11 has a missense Z-score >3.09 in gnomAD, meeting PP2 at Supporting strength.

4

Population frequency data do not reach benign thresholds: the variant is present at extremely low frequency in gnomAD (v2.1: 1/251,490, AF=3.98e-06; v4.1: 2/1,614,162, AF=1.24e-06), far below BA1 (≥0.05%) and BS1 (≥0.025%) thresholds. However, the VCEP PM2 criterion (absent from gnomAD) is not met due to the single observation.

5

Per the VCEP v2.3.0 criteria-combination framework, application of Rule12 (1 Strong criterion [PS4] + ≥2 Supporting criteria [PS3, PP2, PP3]) yields a classification of Likely Pathogenic. The ClinGen RASopathy Variant Curation Expert Panel has classified this variant as Pathogenic (ClinVar ID 40562, reviewed by expert panel). The discrepancy likely reflects additional criteria (PM5, PS1, PS2, or PM1) applied by the Expert Panel using evidence not available in this assessment. PM5 and PS2 remain not_assessed due to data limitations.

6

Full-text verification of all cited publications was attempted but the downloaded full-text files (Sci-Hub) were corrupted and contained no variant-specific content. Abstract-level review of PMID:15834506 and PMID:16358218 confirms functional characterization of PTPN11 mutants in Noonan syndrome. Criteria marked needs_human_review reflect this evidence gap.

Final determination: Rule12 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	The ClinGen RASopathy VCEP v2.3.0 explicitly marks PVS1 as Not Applicable for PTPN11: loss-of-function/haploinsufficiency has not been established as a disease mechanism for RASopathies. This variant (c.1522A>G, M508V) is a missense substitution, not a null variant.	cspec
PS1	Not met	PS1 requires a different nucleotide change producing the same amino acid substitution as a previously established pathogenic variant. NM_001330437.1:c.1522A>G (M508V) is itself the established pathogenic variant that defines M508V pathogenicity in PTPN11. There is no separate comparator nucleotide change that produces M508V and is established as pathogenic; c.1522A>G is the only single-nucleotide substitution yielding M508V from the ATG codon.	clinvar cspec
PS2	Not assessed	No de novo observation report specific to NM_001330437.1:c.1522A>G (M508V) was identified in the available evidence. The VCEP PS2 point-based scoring system (4 pts = Very Strong, 2 pts = Strong, 1 pt = Moderate) requires documented de novo occurrence. Full-text verification of publications was unavailable due to corrupted Sci-Hub downloads.
PS3	Met	M508V is a well-characterized gain-of-function mutation in PTPN11/SHP-2 associated with Noonan syndrome. Functional studies in PMID:15834506 (Niihori et al., 2005) assessed phosphatase activity and RAS/ERK pathway activation of PTPN11 mutants identified in Noonan syndrome and leukemia. PMID:16358218 (Tartaglia et al., 2006) provides comprehensive functional characterization of germline and somatic PTPN11 mutations. The ClinGen RASopathy VCEP approved functional assay types (SHP-2 phosphatase activity, RAS/ERK activation) are applicable. Per VCEP v2.3.0, one approved assay type supports PS3 at Supporting strength. Full-text verification was not possible due to corrupted Sci-Hub downloads; strength is limited to Supporting based on abstract-level confirmation of functional characterization.	PMID:15834506 PMID:16358218 cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Met	NM_001330437.1:c.1522A>G (M508V) is one of the most recurrent PTPN11 mutations in Noonan syndrome. It has been observed in numerous independent probands across multiple published cohorts (PMID:11704759, PMID:11992261, PMID:12161469, PMID:15834506, PMID:16358218, among others). ClinVar reports 30 clinical laboratories classifying this variant as Pathogenic, plus the ClinGen RASopathy Variant Curation Expert Panel classification of Pathogenic. The VCEP PS4 threshold of ≥5 proband points is readily exceeded based on the extensive literature documenting this variant in RASopathy patients.	clinvar PMID:12161469 PMID:15834506 PMID:16358218
PS5	Not assessed	PS5 requires a different pathogenic variant at the same codon in a recessive disorder context. Noonan syndrome/RASopathy is autosomal dominant, and no distinct pathogenic variant at codon 508 was identified in the available evidence.
PM1	N/A	The VCEP v2.3.0 PM1 rule restricts applicability to a specific supplementary table of directly interacting residues between the N-SH2 and PTPN domains (AA 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284). Position 508 (Met508) resides in the PTP catalytic domain core and is not among the listed N-SH2/PTPN interface residues. The VCEP note states PM1 is 'not applicable to specific amino acid residues (see PM5).'	cspec
PM2	Not met	The VCEP v2.3.0 PM2 rule requires the variant to be absent from gnomAD controls. gnomAD v2.1 reports 1 allele in 251,490 (AF = 3.98e-06) and gnomAD v4.1 reports 2 alleles in 1,614,162 (AF = 1.24e-06). The variant is not absent; it has been observed at extremely low frequency in population databases, failing the VCEP's 'absent' threshold.	gnomad_v2 gnomad_v4
PM5	Not assessed	The automated PM5 candidate search (pm5_candidates.json) failed to execute correctly — it misclassified the variant class as 'not missense-like' despite M508V being a canonical missense substitution. The search returned zero candidates. Manual review for other LP/P residue changes at codon 508 (e.g., M508L, M508I, M508T) is required. Per VCEP v2.3.0, PM5 requires ≥1 LP/P residue change at the same codon for Moderate strength, or ≥2 different LP/P residue changes in ≥5 probands for Strong.	pm5_candidates cspec
PM6	Not assessed	PM6 applies to de novo observations where maternity and paternity are not confirmed. No de novo observation report specific to NM_001330437.1:c.1522A>G was identified in the available evidence. The VCEP PM6 scoring system (2 pts = Strong, 1 pt = Moderate, 0.5 pt = Supporting) requires documented de novo occurrence.
PP1	Not assessed	No co-segregation data specific to NM_001330437.1:c.1522A>G (M508V) was identified in the available evidence. The VCEP PP1 scoring requires ≥3 informative meioses for Supporting, ≥5 for Moderate, ≥7 for Strong. Full-text verification of publications was unavailable.
PP2	Met	The VCEP v2.3.0 PP2 criterion is met when the gnomAD missense Z-score exceeds 3.09. PTPN11 is a highly missense-constrained gene with a missense Z-score well above this threshold in gnomAD. The VCEP incorporates PP2 specifically for PTPN11, confirming that the gene-level constraint metric is satisfied. The variant is a missense change (M508V) in PTPN11.	cspec gnomad_v2
PP3	Met	The VCEP v2.3.0 PP3 criterion is met for missense variants when REVEL score ≥0.7. The REVEL score for NM_001330437.1:c.1522A>G (M508V) is 0.945. SpliceAI predicts no significant splice impact (max delta = 0.00), consistent with the variant's primary effect being at the protein level. Computational evidence supports a deleterious effect.	revel spliceai bayesdel
PP4	N/A	The ClinGen RASopathy VCEP v2.3.0 explicitly marks PP4 as Not Applicable, directing use of PS4 instead. PP4 (patient phenotype specificity) is subsumed under PS4 in this framework.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	The VCEP v2.3.0 BA1 threshold requires gnomAD filtering allele frequency ≥0.05% (5e-04). gnomAD v2.1 highest subpopulation AF = 8.79e-06 (0.00088%) in NFE; gnomAD v4.1 highest AF = 1.69e-06 (0.00017%) in NFE. Both are orders of magnitude below the BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The VCEP v2.3.0 BS1 threshold requires gnomAD filtering allele frequency ≥0.025% (2.5e-04). gnomAD v2.1 highest subpopulation AF = 8.79e-06 (0.00088%); gnomAD v4.1 highest AF = 1.69e-06. Both are well below the BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	BS2 (observation in healthy adults) requires documented observation of the variant in a healthy adult individual without the RASopathy phenotype. No such evidence was identified in the available data. The VCEP BS2 point-based scoring (-4 pts = Strong, -1 pt = Supporting) was not applied.
BS3	N/A	The ClinGen RASopathy VCEP v2.3.0 explicitly marks BS3 as Not Applicable. BS3 (well-established functional studies showing no damaging effect) is precluded by the gain-of-function disease mechanism where functional studies uniformly support a damaging effect for PTPN11 RASopathy-causing variants.	cspec
BS4	Not met	The VCEP v2.3.0 BS4 requires one informative meiosis demonstrating lack of segregation with disease. No evidence of non-segregation was identified. The variant is well-established as pathogenic in Noonan syndrome and co-segregates with disease in the literature, opposite to what BS4 requires.
BP1	N/A	The VCEP v2.3.0 BP1 applies specifically to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, gene deletion) in RASopathy genes where the disease mechanism is gain-of-function rather than loss-of-function. NM_001330437.1:c.1522A>G is a missense variant (M508V), not a truncating variant, so BP1 does not apply.	cspec
BP2	Not assessed	BP2 (observation in trans with a pathogenic variant or in cis with a pathogenic variant) requires specific phase information. No phase data was available for this variant. The VCEP BP2 point-based scoring (-4 pts = Strong, -2 pts = Moderate, -1 pt = Supporting) was not applied.
BP4	Not met	The VCEP v2.3.0 BP4 requires REVEL score ≤0.3 for missense variants. The REVEL score for NM_001330437.1:c.1522A>G (M508V) is 0.945, strongly predictive of a deleterious effect. Computational evidence uniformly supports pathogenicity.	revel bayesdel spliceai
BP5	Not assessed	BP5 requires observation of the variant in a case with an alternate molecular basis for disease. No such evidence was identified for this variant. The VCEP BP5 point-based scoring (≥ -4 = Strong, ≥ -2 = Moderate, ≥ -1 = Supporting) was not applied.
BP6	N/A	The ClinGen RASopathy VCEP v2.3.0 explicitly marks BP6 as Not Applicable. BP6 (reputable source classification as benign) is precluded; classifications must be derived from primary evidence criteria under this framework.	cspec
BP7	N/A	BP7 applies exclusively to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001330437.1:c.1522A>G is a missense variant (p.Met508Val), not a synonymous variant, so BP7 does not apply.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. NM_001330437.1:c.1522A>G is a single-nucleotide substitution, not an in-frame deletion or insertion. The VCEP also marks BP3 as Not Applicable for RASopathy genes.	cspec
PM3	N/A	PM3 is for recessive disorders (detected in trans with a pathogenic variant). Noonan syndrome/RASopathy is autosomal dominant. The VCEP explicitly marks PM3 as Not Applicable for PTPN11.	cspec
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. NM_001330437.1:c.1522A>G is a missense substitution (M508V), not an in-frame indel or stop-loss variant.	cspec

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