Variant classification summary

NM_002834.4:c.1508G>T

PTPN11 · NP_002825.3:p.(Gly503Val) · NM_002834.4

GRCh37: chr12:112926888 G>T · GRCh38: chr12:112489084 G>T

Gene: PTPN11 Transcript: NM_002834.4

Final call

Pathogenic

PS3 strong PM1 moderate PM2 moderate PP2 supporting PP3 supporting

Variant details

Gene

PTPN11

Transcript

NM_002834.4

Protein

NP_002825.3:p.(Gly503Val)

gnomAD AF

ClinVar

other

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002834.4:c.1508G>T (p.Gly503Val) in PTPN11 is a missense variant in the PTP catalytic domain of SHP-2, located within a statistically significant hotspot.

2

This variant is completely absent from population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).

3

Functional studies using a VCEP-approved SHP-2 phosphatase activity assay demonstrated 1.4-fold increased catalytic activity for G503V compared to wild-type, consistent with the gain-of-function mechanism of RASopathies (PS3).

4

The variant resides in the PTP catalytic domain at a residue adjacent to known pathogenic variants (S502, M504) and within a mutational hotspot (PM1).

5

PP2 applies per VCEP specification as PTPN11 is a RASopathy gene with missense variants as a common disease mechanism.

6

Multiple computational tools predict a deleterious effect: REVEL score 0.989, BayesDel score 0.608, supporting PP3.

7

PS3 was applied at strong per VCEP specifications; the variant was directly tested in an approved SHP-2 phosphatase assay and showed increased activity. Modest activation (1.4-fold) compared to other pathogenic PTPN11 variants noted but does not preclude application per VCEP rules.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

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	PVS1 is not applicable per ClinGen RASopathy VCEP v1.0; loss-of-function has not been clearly established as a disease mechanism for RASopathies and this is a missense variant.	cspec
PS1	Not met	No previously established pathogenic variant with the identical amino acid change (p.Gly503Val) has been classified as pathogenic per VCEP criteria in a germline RASopathy context.	clinvar PMID:15834506
PS2	Not met	No de novo occurrence with confirmed parentage has been reported for this variant.
PS3	Met	SHP-2 phosphatase activity assay (VCEP-approved gene-specific functional assay) demonstrated 1.4-fold increased phosphatase activity for G503V compared to wild-type SHP-2 in COS7 cells, consistent with gain-of-function mechanism of RASopathy.	PMID:15834506 vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not met	No independent occurrences meeting VCEP proband-counting thresholds (>=1 for supporting, >=3 for moderate, >=5 for strong) are available. ClinVar contains only one submission with classification 'other' in a somatic context.	clinvar PMID:26822237 PMID:19681119
PS5	N/A	PS5 is not defined in the ClinGen RASopathy VCEP v1.0 criteria.	cspec
PM1	Met	Variant is located at codon 503 in the PTP catalytic domain of SHP-2, a critical functional domain. Residue is within a statistically significant hotspot; adjacent residues S502 and M504 are listed as pathogenic validation controls in the VCEP functional studies spreadsheet.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM2	Met	Variant is completely absent from all population databases per VCEP requirement (gnomAD v2.1, v4.1, and gnomAD-Canada).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at codon 503 has been established per VCEP criteria. Despite the variant being a missense change (G503V), no comparator pathogenic variant at this residue exists in ClinVar or the literature.
PM6	Not met	No confirmed de novo occurrence has been reported for this variant.
PP1	Not met	No cosegregation data available. VCEP requires at least three informative meioses for PP1 at supporting level.
PP2	Met	VCEP specifies PP2 is applicable to all RASopathy genes described and curated. PTPN11 is a RASopathy gene with a low rate of benign missense variation and missense variants are a common disease mechanism.	cspec
PP3	Met	Multiple lines of computational evidence support a deleterious effect: REVEL score 0.989 (highly deleterious), BayesDel score 0.608, statistically significant hotspot at this residue. SpliceAI predicts no splice impact (max delta 0.19) and does not contribute to PP3.	revel bayesdel spliceai
PP4	N/A	VCEP explicitly states this criterion is not applicable to the RASopathies; proband counting is handled via PS4.	cspec
PP5	N/A	VCEP explicitly states this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	Allele frequency is 0% in gnomAD, well below the VCEP-approved BA1 threshold of >=0.05%.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency is 0% in gnomAD, well below the VCEP-approved BS1 threshold of >=0.025%.	gnomad_v2 gnomad_v4
BS2	Not met	VCEP requires well-phenotyped family members (>3 instances) for BS2 application; no such data available. General population data cannot substitute.
BS3	Not met	Functional data demonstrates increased SHP-2 phosphatase activity (1.4-fold, gain-of-function), inconsistent with a benign effect on protein function. BS3 requires functional studies showing no damaging effect; the available data supports pathogenicity.	PMID:15834506
BS4	Not met	No segregation data available for this variant.
BP1	N/A	BP1 per VCEP applies only to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, exon/gene deletions) in RASopathy genes without established LOF correlation. This is a missense variant.	cspec
BP2	Not met	No evidence of the variant being observed in trans with a pathogenic variant or in cis with a pathogenic variant.
BP4	Not met	Computational evidence does not suggest no impact on gene product. REVEL 0.989 strongly predicts deleterious effect, BayesDel 0.608 is borderline-deleterious, and the residue is a statistically significant hotspot. These findings contradict BP4 and instead support PP3.	revel bayesdel
BP5	Not met	No alternate molecular basis for disease has been identified in a case harboring this variant.
BP6	N/A	VCEP explicitly states this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 applies to synonymous (silent) variants and intronic/non-coding variants. This is a missense variant (p.Gly503Val).

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