Variant classification summary

NM_002834.5:c.922A>G

PTPN11 · NP_002825.3:p.(Asn308Asp) · NM_002834.5

GRCh37: chr12:112915523 A>G · GRCh38: chr12:112477719 A>G

Gene: PTPN11 Transcript: NM_002834.5

Final call

VUS

PS3 moderate PS4 moderate PP3 supporting PP5 supporting

Variant details

Gene

PTPN11

Transcript

NM_002834.5

Protein

NP_002825.3:p.(Asn308Asp)

gnomAD AF

7.443282189714377e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Moderate: p.Asn308Asp shows increased phosphatase activity and prolonged ERK2 activation in two approved assay types.

2

PS4 Moderate: the variant occurred in multiple unrelated Noonan syndrome patients and was absent from more than 200 controls in one report.

3

PP3 Supporting: REVEL 0.838 exceeds the PTPN11 VCEP missense threshold of 0.7.

4

PP5 Supporting: recorded in the adjudicated criteria, but it does not satisfy an additional VCEP combination rule.

Final determination: No pathogenic or benign combination rule in the ClinGen RASopathy Expert Panel PTPN11 Version 2.3 framework is satisfied by PS3 moderate, PS4 moderate, PP3 supporting, and PP5 supporting; therefore the call is VUS.

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	Not applicable: the VCEP explicitly excludes PVS1 for the RASopathy spectrum, and c.922A>G is a missense p.Asn308Asp substitution.	cspec pvs1_variant_assessment
PS1	Not met	Not met: zero alternate-nucleotide variants producing the same pathogenic p.Asn308Asp amino-acid change were identified.	pm5_candidates
PS2	Not assessed	Not assessed: available reports do not verify parental testing or provide auditable de novo evidence sufficient to assign the VCEP's 1-, 2-, or 4-point PS2 levels.	cspec PMID:11704759
PS3	Met	Met at Moderate: p.N308D shows increased phosphatase activity and prolonged ERK2 activation in two different VCEP-approved assay types.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:14974085 PMID:15834506
PS4	Met	Met at Moderate: the variant occurred in multiple unrelated Noonan syndrome patients and was absent from more than 200 controls, satisfying the VCEP rare-variant pathway.	cspec PMID:11704759 PMID:11992261 PMID:12634870 PMID:15001945
PM1	Not met	Not met: residue 308 is outside every VCEP-approved directly interacting N-SH2/PTP PM1 region, whose highest listed endpoint is 284.	cspec
PM2	Not met	Not met: the variant is present in gnomAD v2.1 at 3/251440 alleles and gnomAD v4.1 at 12/1612192 alleles, contrary to the VCEP absence requirement.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTPN11 VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: PM4 requires an in-frame indel or stop-loss protein length change, whereas c.922A>G produces missense p.Asn308Asp.	cspec pvs1_variant_assessment
PM5	Not met	Not met: zero different likely pathogenic residue changes at codon 308 were identified, below the VCEP minimum of one for Moderate PM5.	pm5_candidates
PM6	Not assessed	Not assessed: no verified de novo occurrence without confirmed parental testing is available to assign the VCEP's 0.5-, 1-, or 2-point PM6 levels.	cspec
PP1	Not assessed	Not assessed: cosegregation is reported, but the number of informative meioses needed for the VCEP's 3-, 5-, or 7-meiosis thresholds is not documented.	cspec PMID:11992261
PP2	Not assessed	Not assessed: the VCEP requires a PTPN11 missense z score >3.09, but no missense z score is available.	cspec
PP3	Met	Met: REVEL 0.838 meets the PTPN11 VCEP PP3 missense threshold of ≥0.7.	cspec revel
PP4	N/A	Not applicable: the PTPN11 VCEP explicitly marks PP4 as not applicable and directs phenotype evidence to PS4.	cspec
PP5	Met	Not applicable: the PTPN11 VCEP prohibits use of PP5, regardless of published pathogenic classifications.	cspec clinvar
BA1	Not met	Not met: the highest available gnomAD population AF is 0.01630%, below the VCEP BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest available gnomAD population AF is 0.01630%, below the VCEP BS1 threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes, but the VCEP provides only point assignments and no available evidence establishes the required BS2 observation.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the PTPN11 VCEP Version 2.3 explicitly marks BS3 as not applicable.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative non-segregating meiosis or unaffected tested relative carrying the variant is documented for the VCEP's one-meiosis BS4 rule.	cspec PMID:11992261
BP1	N/A	Not applicable: BP1 is restricted to specified truncating variants, whereas this variant is the missense change p.Asn308Asp.	cspec
BP2	Not assessed	Not assessed: no documented cis/trans second pathogenic variant or BP2 point assignment is available for this variant.	cspec PMID:11704759 PMID:11992261
BP3	N/A	Not applicable: BP3 is limited to in-frame indels in benign repetitive regions, while c.922A>G is a missense p.Asn308Asp substitution.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.838 exceeds the PTPN11 VCEP BP4 missense threshold of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant or BP5 point value is documented, so the VCEP's ≥ (-1), ≥ (-2), or ≥ (-4) thresholds cannot be tested.	cspec
BP6	N/A	Not applicable: the PTPN11 VCEP explicitly prohibits use of BP6 for this framework.	cspec
BP7	N/A	Not applicable: c.922A>G is a missense variant, whereas BP7 covers synonymous, eligible intronic, or non-coding variants.	cspec

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