Variant classification summary

NM_001330437.1:c.215C>T

PTPN11 · NP_001317366.1:p.(Ala72Val) · NM_001330437.1

GRCh37: chr12:112888199 C>T · GRCh38: chr12:112450395 C>T

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Pathogenic

PS1 strong PS3 supporting PS4 supporting PM1 moderate PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Ala72Val)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS1 (Strong): p.Ala72Val is an established pathogenic amino acid substitution in PTPN11, meeting the RASopathy VCEP criterion for same amino acid change as a previously established pathogenic variant.

2

PM1 (Moderate): Residue 72 lies within the N-SH2/PTPN domain interaction interface (amino acids 69-77), a critical functional domain defined by the RASopathy VCEP as a known mutational hotspot.

3

PM2 (Supporting): The variant is absent from gnomAD population controls (v2.1 and v4.1), meeting the VCEP threshold for absence from controls.

4

PP2 (Supporting): PTPN11 has a low rate of benign missense variation with a gnomAD missense Z-score >3.09, consistent with a gene where missense variants are a common disease mechanism.

5

PP3 (Supporting): In silico prediction with a REVEL score of 0.921 supports a deleterious effect on protein function, exceeding the VCEP threshold of ≥0.7.

6

PS3_Supporting: Functional studies demonstrate gain-of-function activity of the p.Ala72Val SHP-2 mutant, as curated by OncoKB and reported in published functional analyses of PTPN11 mutations.

7

PS4_Supporting: The variant has been observed in multiple individuals with Noonan syndrome/RASopathy phenotypes, meeting the VCEP threshold of ≥1 point for PS4 at Supporting strength.

8

Final classification: Pathogenic per RASopathy VCEP v2.3.0, Rule8 (1 Strong criterion [PS1] + 1 Moderate criterion [PM1] + ≥4 Supporting criteria [PS3_Supporting, PS4_Supporting, PM2_Supporting, PP2, PP3]).

Final determination: Rule8 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 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	Null variants are not an established disease mechanism for RASopathies per the RASopathy VCEP v2.3.0; PVS1 is explicitly not applicable for PTPN11 under this framework.	cspec
PS1	Met	p.Ala72Val is an established pathogenic amino acid substitution in PTPN11, reported in multiple individuals with Noonan syndrome and curated as Pathogenic in ClinVar (VariationID 41443). The RASopathy VCEP rule for PS1 is met: same amino acid change as a previously established pathogenic variant in PTPN11.	cspec clinvar
PS2	Not met	No confirmed de novo occurrence data with confirmed maternity/paternity was identified for this variant in the available evidence.
PS3	Met	Functional studies demonstrate that the p.Ala72Val substitution results in gain-of-function activity of SHP-2. OncoKB curates this variant as Likely Oncogenic (Likely Gain-of-function). Multiple publications have characterized the functional consequences of PTPN11 mutations at residue Ala72, including phosphatase activity assays. At least one approved functional assay supports a damaging effect, meeting the VCEP PS3 Supporting threshold (one approved assay).	cspec oncokb PMID:15834506 PMID:16358218
PS4	Met	The variant has been observed in multiple individuals with Noonan syndrome / RASopathy phenotypes. Kosaki et al. (2002) reported PTPN11 mutations including this variant in a cohort of Japanese Noonan syndrome patients. The variant meets the VCEP PS4 Supporting threshold (≥1 point) based on RASopathy phenotype observations.	clinvar cspec PMID:12161469
PS5	N/A	PS5 is not defined in the RASopathy VCEP v2.3.0; PM1 and PM5 cover the equivalent evidence domain (mutational hotspot and same-residue missense).
PM1	Met	Residue 72 lies within the N-SH2/PTPN domain interaction interface (AA 69-77), which is a critical and well-established functional domain defined in the RASopathy VCEP supplementary table. This domain is a known hotspot for pathogenic missense variants in PTPN11.	cspec
PM2	Met	The variant is absent from population controls in gnomAD v2.1 and v4.1, meeting the RASopathy VCEP PM2 Supporting threshold (absent from controls).	gnomad_v2 gnomad_v4 cspec
PM5	Not met	No confirmed pathogenic or likely pathogenic missense variant at a different residue change within the same codon (codon 72) was identified in the available comparator search. The PM5 candidate pipeline returned zero candidates.	pm5_candidates
PM6	Not met	No assumed de novo observations were identified for this variant in the available evidence.
PP1	Not met	No co-segregation data (informative meioses) were identified for this variant in the available evidence.
PP2	Met	PTPN11 has a low rate of benign missense variation with a gnomAD missense Z-score >3.09, meeting the RASopathy VCEP PP2 Supporting threshold. Missense variants are a common mechanism of disease in this gene.	cspec
PP3	Met	The REVEL score for this variant is 0.921, which exceeds the VCEP threshold of ≥0.7 for pathogenic computational prediction. SpliceAI predicts no significant splice impact (max delta = 0.02), confirming the effect is at the protein level.	revel cspec
PP4	N/A	PP4 is not applicable per the RASopathy VCEP v2.3.0; see PS4 for phenotype-based evidence.	cspec
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee, as specified in the RASopathy VCEP v2.3.0.	cspec
BA1	Not met	The variant is absent from gnomAD. The VCEP BA1 threshold of ≥0.05% filtering allele frequency is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD. The VCEP BS1 threshold of ≥0.025% filtering allele frequency is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No observations of this variant in healthy adult individuals were identified. The variant is absent from population databases, consistent with its absence in unaffected controls.
BS3	N/A	BS3 is not applicable per the RASopathy VCEP v2.3.0 for this variant type; functional evidence supports a damaging, not benign, effect.	cspec
BS4	Not met	No evidence of lack of segregation in affected family members was identified for this variant.
BP1	N/A	BP1 is applicable only to truncating variants in genes where gain-of-function is the disease mechanism per the RASopathy VCEP. This variant is a missense substitution, not a truncating variant.	cspec
BP2	Not met	No evidence of this variant being observed in trans with a pathogenic variant or in cis with a pathogenic variant was identified.
BP4	Not met	The REVEL score for this variant is 0.921, which exceeds the VCEP BP4 threshold of ≤0.3. Multiple computational predictors support a deleterious effect rather than a benign one.	revel cspec
BP5	Not met	No alternative molecular cause for a RASopathy in a different gene was identified in cases carrying this variant.
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee, as specified in the RASopathy VCEP v2.3.0.	cspec
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. NM_001330437.1:c.215C>T is a missense variant (p.Ala72Val), not a synonymous variant.

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