Variant classification summary

NM_002834.4:c.200G>A

PTPN11 · NP_002825.3:p.(Gly67Glu) · NM_002834.4

GRCh37: chr12:112888184 G>A · GRCh38: chr12:112450380 G>A

Gene: PTPN11 Transcript: NM_002834.4

Final call

VUS

PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTPN11

Transcript

NM_002834.4

Protein

NP_002825.3:p.(Gly67Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002834.4:c.200G>A (p.Gly67Glu) in PTPN11 is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada.

2

PTPN11 has a gnomAD missense z-score >3.09, indicating strong constraint against missense variation and supporting pathogenicity under PP2 at Supporting strength per RASopathy VCEP specifications.

3

REVEL in silico prediction score is 0.89, exceeding the VCEP threshold of 0.70 for PP3 at Supporting strength, consistent with a deleterious effect on protein function.

4

The variant does not meet criteria for PS1 (no known pathogenic G67E), PM1 (position 67 is outside the VCEP-defined critical functional domain residue set), PM5 (no pathogenic comparators at codon 67), or any other pathogenic criterion above Supporting strength.

5

With PM2_Supporting, PP2_Supporting, and PP3_Supporting met (three Supporting-level pathogenic criteria), the variant does not satisfy any Pathogenic or Likely Pathogenic combination rule in the RASopathy VCEP Version 2.3.0 framework. No Likely Pathogenic rule is triggered with fewer than four Supporting criteria in the absence of Moderate or Strong evidence. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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 for PTPN11 Version 2.3.0 declares PVS1 not applicable because loss of function is not an established disease mechanism for RASopathies. Additionally, NM_002834.4:c.200G>A (p.Gly67Glu) is a missense variant, not a null variant.	cspec
PS1	Not met	PS1 requires the same amino acid change (p.Gly67Glu) as a previously established pathogenic variant in PTPN11. No pathogenic or likely pathogenic p.Gly67Glu variant was identified in ClinVar or the literature. The variant is absent from ClinVar entirely.	clinvar
PS2	Not met	PS2 requires de novo occurrence with confirmed maternity and paternity in a patient with a RASopathy phenotype. No de novo reports were identified for this variant in ClinVar or the literature.
PS3	Not met	PS3 requires well-established in vitro or in vivo functional studies supportive of a damaging effect using VCEP-approved assays. The VCEP-approved functional studies spreadsheet was searched and does not include p.Gly67Glu (G67E) among tested variants in any approved assay (RAS Activation, MEK Activation, ERK Activation, or SHP-2 Phosphatase Activity). OncoKB reports no variant-specific reviewed functional evidence. No publications with functional data for this variant were identified.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not met	PS4 requires significantly increased prevalence in affected individuals versus controls, assessed via point-based scoring in the RASopathy VCEP. The variant is absent from ClinVar with no reported probands. Zero points are scored.	clinvar
PS5	N/A	Skipped per user directive — not in the assess list for this adjudication.
PM1	Not met	PM1 in the RASopathy VCEP for PTPN11 is applicable only to specific directly interacting residues between N-SH2 and PTPN domains: AA 4, 7–9, 58–63, 69–77, 247, 251, 255, 256, 258, 261, 265, 278–281, 284. The variant p.Gly67Glu is at position 67, which lies between the listed ranges (58–63 and 69–77) and is not included in the VCEP-defined functional domain residue set.	cspec
PM2	Met	The variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per RASopathy VCEP specifications, PM2 is downgraded to Supporting strength when the variant is absent from controls.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PTPN11 RASopathies follow autosomal dominant inheritance; PM3 (detected in trans for recessive disorders) is not applicable per the RASopathy VCEP.	cspec
PM4	N/A	PM4 applies to protein length changes (in-frame deletions/insertions, stop-loss). NM_002834.4:c.200G>A is a missense substitution, not a protein-length-altering variant.
PM5	Not met	PM5 requires a different pathogenic or likely pathogenic missense change at the same codon (Gly67). No such comparator variants were identified at codon 67 in ClinVar or any evidence source. The automated PM5 candidate search returned zero same-residue candidates.	pm5_candidates
PM6	Not met	PM6 requires assumed de novo occurrence without confirmation of paternity and maternity. No de novo observations for this variant were identified in ClinVar or the literature.
PP1	Not met	PP1 requires co-segregation with disease in multiple affected family members. No family or segregation data are available for this variant.
PP2	Met	PTPN11 has a gnomAD missense z-score substantially exceeding 3.09, indicating strong constraint against missense variation. Per RASopathy VCEP specifications, a missense z-score >3.09 qualifies for PP2 at Supporting strength.	gnomad_v2
PP3	Met	REVEL score is 0.89, which exceeds the RASopathy VCEP threshold of ≥0.7 for PP3 at Supporting strength. Additionally, SpliceAI predicts no significant splice impact (max delta score 0.02), so splicing is not a confounding factor.	revel spliceai
PP4	N/A	The RASopathy VCEP declares PP4 not applicable; phenotype specificity is addressed through PS4 point-based scoring instead.	cspec
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee per the RASopathy VCEP Version 2.3.0.	cspec
BA1	Not met	BA1 requires a gnomAD filtering allele frequency ≥0.05%. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires a gnomAD filtering allele frequency ≥0.025%. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 requires observation in healthy adult individuals. The variant is absent from all population databases, with no observations in any individual (affected or unaffected).	gnomad_v2 gnomad_v4
BS3	N/A	The RASopathy VCEP declares BS3 not applicable, as functional studies showing no damaging effect are not part of the approved framework.	cspec
BS4	Not met	BS4 requires lack of segregation in affected family members. No family or segregation data are available for this variant.
BP1	N/A	BP1 in the RASopathy VCEP applies specifically to truncating variants (nonsense, frameshift, canonical splice sites) in genes where gain-of-function is the disease mechanism. NM_002834.4:c.200G>A is a missense variant (p.Gly67Glu), not a truncating variant.	cspec
BP2	Not met	BP2 awards points for an alternative molecular cause of a RASopathy in the same gene or in conjunction with BP5. No alternative molecular cause has been identified alongside this variant.
BP3	N/A	Skipped per user directive — BP3 is trivially not applicable (in-frame deletions/insertions in repetitive regions; variant is a missense substitution).
BP4	Not met	BP4 requires REVEL score ≤0.3 for missense variants per RASopathy VCEP specifications. The REVEL score for this variant is 0.89, which does not meet the BP4 threshold.	revel
BP5	Not met	BP5 awards points for an alternative molecular cause of a RASopathy in a different gene when the phenotype is consistent. No alternative molecular cause has been identified.
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee per the RASopathy VCEP Version 2.3.0.	cspec
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. NM_002834.4:c.200G>A is a missense variant (p.Gly67Glu), not a synonymous variant.

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