Variant classification summary

NM_002834.4:c.179G>T

PTPN11 · NP_002825.3:p.(Gly60Val) · NM_002834.4

GRCh37: chr12:112888163 G>T · GRCh38: chr12:112450359 G>T

Gene: PTPN11 Transcript: NM_002834.4

Final call

Likely Pathogenic

PS3 supporting PM1 moderate PM2 moderate PM5 moderate PP2 supporting PP3 supporting

Variant details

Gene

PTPN11

Transcript

NM_002834.4

Protein

NP_002825.3:p.(Gly60Val)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002834.4:c.179G>T (p.Gly60Val) in PTPN11 is a missense variant in the N-SH2 domain, a critical functional domain that regulates SHP2 autoinhibition.

2

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

3

Functional studies demonstrate that SHP2 G60V exhibits increased basal phosphatase activity compared to wild-type, consistent with a gain-of-function mechanism in RASopathies (PS3_Supporting).

4

The variant is located at a residue (Gly60) within the N-SH2 domain where multiple pathogenic missense changes have been reported (PM1).

5

A different pathogenic missense change at the same residue, Gly60Ala (c.179G>C), has been reported in Noonan syndrome (PM5).

6

Multiple in silico predictors support a deleterious effect: REVEL score 0.931 and BayesDel score 0.596 (PP3).

7

PP2 is applicable per the RASopathy VCEP specification for all curated RASopathy genes (PP2).

8

This variant has been reported in ClinVar as Pathogenic by 9 clinical laboratories and Likely pathogenic by 2 clinical laboratories (ClinVar variation ID 55797).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of 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 to the RASopathies per the ClinGen RASopathy VCEP v1.0. Loss of function has not been established as a disease mechanism for PTPN11 relative to the RASopathy spectrum. Additionally, c.179G>T (p.Gly60Val) is a missense variant, not a null variant.	cspec
PS1	Not met	PS1 requires the same amino acid change (Gly60Val) to have been previously established as pathogenic via a different nucleotide change. No evidence was found that G60V has been established as pathogenic through an alternate nucleotide substitution.
PS2	Not met	No de novo occurrence with confirmed paternity and maternity was identified for NM_002834.4:c.179G>T in the reviewed literature.
PS3	Met	SHP2 G60V demonstrated increased basal phosphatase activity compared to wild-type SHP2 in a quantitative DiFMUP-based phosphatase assay (PMID:30375388). This assay type (SHP-2 Phosphatase Activity) is an approved functional assay for PTPN11 per the RASopathy VCEP supplemental material. The VCEP spreadsheet assigns PS3_Supporting strength for approved functional studies. G60V showed intermediate activation between F285S and S502P/E76K and conferred resistance to allosteric inhibition by SHP099 in cellular assays, consistent with a gain-of-function mechanism.	PMID:30375388 cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not met	While ClinVar contains 11 clinical laboratory submissions classifying this variant as Pathogenic (9) or Likely pathogenic (2), these represent submissions, not independently ascertained proband occurrences. No literature was identified reporting ≥1 independent occurrence of NM_002834.4:c.179G>T in a RASopathy patient. Notably, PMID:11992261 reported G60A (c.179G>C) but not G60V.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP criterion and is not included in the RASopathy VCEP criteria.
PM1	Met	Gly60 is located in the N-SH2 domain of SHP2, a critical functional domain that forms the autoinhibitory interface with the PTP domain. Multiple pathogenic missense changes have been reported at this residue (G60A, G60C, G60V), and disruption of Gly60 destabilizes the autoinhibited conformation, leading to constitutive phosphatase activation. The N-SH2 domain is a well-established critical functional domain in SHP2.	PMID:11992261 PMID:30375388
PM2	Met	NM_002834.4:c.179G>T is completely absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the VCEP requirement of complete absence from all population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Met	A different missense change at the same residue, Gly60Ala (c.179G>C, p.Gly60Ala), has been previously reported as a pathogenic variant in Noonan syndrome (PMID:11992261). Both G60A and G60V are non-conservative substitutions at a glycine residue critical to the autoinhibitory interface. Under the RASopathy VCEP, one established pathogenic missense at the same residue qualifies for PM5 at moderate strength.	PMID:11992261
PM6	Not met	No assumed or confirmed de novo occurrence of NM_002834.4:c.179G>T was identified in the reviewed literature.
PP1	Not met	No co-segregation data with informative meioses is available for this variant in the reviewed literature.
PP2	Met	The RASopathy VCEP explicitly states that PP2 is applicable to all RASopathy genes described and curated in the specification. PTPN11 is a RASopathy gene, and c.179G>T is a missense variant in a gene where missense variants are a common mechanism of disease.	cspec
PP3	Met	Multiple lines of computational evidence support a deleterious effect: REVEL score of 0.931 (strongly deleterious) and BayesDel score of 0.596 (deleterious). Both in silico predictors independently suggest a damaging effect on the gene product. SpliceAI predicts no significant splice impact (max delta score 0.05), indicating the effect is at the protein level.	revel bayesdel spliceai
PP4	N/A	PP4 is not applicable to the RASopathies per the ClinGen RASopathy VCEP v1.0. The VCEP directs use of PS4 for proband counting instead.	cspec
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the RASopathy VCEP.	cspec
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the VCEP BA1 threshold of ≥0.05%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the VCEP BS1 threshold of ≥0.025%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The VCEP specifies that general population data should not be used for BS2 in RASopathies due to variable expressivity. No well-phenotyped healthy family members (≥3 instances) have been identified with this variant.	cspec
BS3	Not met	Functional data from PMID:30375388 demonstrates that SHP2 G60V has increased basal phosphatase activity compared to wild-type, consistent with a gain-of-function mechanism. No functional studies suggest a benign or no-effect outcome for this variant.	PMID:30375388
BS4	Not met	No segregation data demonstrating lack of segregation in affected family members is available for this variant.
BP1	N/A	BP1 applies only to truncating variants in genes without established LOF correlation to disease per the RASopathy VCEP. This is a missense variant (p.Gly60Val).	cspec
BP2	Not met	No data available on whether this variant has been observed in trans with a pathogenic variant or in cis with a pathogenic variant in any inheritance pattern.
BP3	N/A	Not an in-frame deletion/insertion in a repetitive region.
PM3	N/A	PM3 is not applicable to the RASopathies per the ClinGen RASopathy VCEP v1.0. RASopathies are autosomal dominant disorders.	cspec
PM4	N/A	Protein length changes due to in-frame deletions/insertions or stop-loss variants are not applicable. This is a missense substitution.
BP4	Not met	Multiple lines of computational evidence (REVEL 0.931, BayesDel 0.596) support a deleterious effect on the gene product rather than no impact. BP4 requires evidence suggesting no impact.	revel bayesdel
BP5	Not met	No evidence was identified that this variant has been found in a case with an alternate molecular basis for disease.
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the RASopathy VCEP.	cspec
BP7	N/A	BP7 applies only to synonymous (silent) variants or intronic/non-coding variants. NM_002834.4:c.179G>T is a missense variant (p.Gly60Val).

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