Variant classification summary

NM_001330437.1:c.209A>G

PTPN11 · NP_001317366.1:p.(Lys70Arg) · NM_001330437.1

GRCh37: chr12:112888193 A>G · GRCh38: chr12:112450389 A>G

Gene: PTPN11 Transcript: NM_001330437.1

Final call

VUS

PM1 moderate PP5 supporting

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Lys70Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTPN11 c.209A>G (p.Lys70Arg) variant has been reported in ClinVar as Pathogenic by the ClinGen RASopathy Variant Curation Expert Panel and was also reported in a patient with Noonan syndrome in a published cohort.

2

This variant was absent from gnomAD v2.1 and is present only 2 times among 1613656 alleles in gnomAD v4.1 (AF 1.23942e-06; 0.00012%), which is far below the BS1 threshold of 0.025% and the BA1 threshold of 0.05%.

3

The affected Lys70 residue falls within the PTPN11 critical N-SH2/PTP interaction region explicitly designated by the RASopathy specification for PM1.

4

Available computational evidence does not meet PP3 or BP4 thresholds because REVEL is 0.668, BayesDel is 0.00798395, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.

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	This is a missense variant, and the PTPN11 RASopathy specification marks PVS1 as not applicable for this variant type.	cspec pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant causing the same amino acid change by a different nucleotide change was identified in the reviewed ClinVar evidence for Lys70Arg.	clinvar cspec
PS2	Not assessed	One published Noonan syndrome cohort reported this variant in a sporadic case and stated that identified mutations were de novo, but the available evidence does not provide enough verified parentage and phenotype-specific scoring detail here to assign PS2 confidently.	PMID:29084544 cspec
PS3	Not assessed	Approved functional assay classes for PTPN11 are listed by the RASopathy VCEP, but no directly verified variant-specific functional result for p.(Lys70Arg) was identified in the reviewed evidence, so PS3 cannot be assigned at this stage.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PS4	Not assessed	This variant has been reported in ClinVar and in at least one published Noonan syndrome cohort, but the number of unrelated affected probands and the RASopathy PS4 point total could not be verified from the available evidence.	clinvar PMID:29084544 cspec
PM1	Met	Lys70 lies within the PTPN11 N-SH2/PTP interaction interface, and the RASopathy specification explicitly lists residues 69-77 as a critical functional region for PM1 use.	cspec
PM2	Not met	PM2_Supporting requires absence from gnomAD, but this variant is present in gnomAD v4.1 at 2/1613656 alleles (AF 1.23942e-06; 0.00012%), even though it was absent from gnomAD v2.1.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the PTPN11 RASopathy specification for this disorder framework.	cspec
PM4	N/A	This variant is a missense substitution and does not cause an in-frame length change or stop-loss event, so PM4 does not apply.	cspec
PM5	Not met	No different pathogenic missense change at codon 70 was identified in the reviewed ClinVar evidence, so the same-codon requirement for PM5 was not met.	clinvar cspec
PM6	Not assessed	A published Noonan syndrome cohort reported this variant in a sporadic case and stated that identified mutations were de novo, but the available evidence does not provide enough detail on parentage confirmation and scoring to assign PM6 confidently.	PMID:29084544 cspec
PP1	Not assessed	No informative segregation data were identified for this variant, so PP1 could not be assessed.	cspec
PP2	Not assessed	PP2 can be used for PTPN11 missense variants when the gnomAD missense z score is greater than 3.09, but a verified gene-level missense z score was not available in the reviewed evidence.	cspec
PP3	Not met	PP3 requires REVEL at or above 0.7 for missense variants, but the REVEL score is 0.668. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, and the available BayesDel score of 0.00798395 does not overcome the unmet REVEL threshold in this framework.	revel bayesdel spliceai cspec
PP4	N/A	PP4 is not applicable in the PTPN11 RASopathy specification for this disorder framework.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	BA1 requires a gnomAD filtering allele frequency of at least 0.05%, but the observed gnomAD v4.1 allele frequency is 1.23942e-06 (0.00012%), which is far below this threshold.	gnomad_v4 cspec
BS1	Not met	BS1 requires a gnomAD filtering allele frequency of at least 0.025%, but the observed gnomAD v4.1 allele frequency is 1.23942e-06 (0.00012%), which is well below this threshold.	gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals at a level that would satisfy BS2.	cspec
BS3	N/A	BS3 is not applicable in the PTPN11 RASopathy specification for this disorder framework.	cspec
BS4	Not assessed	No non-segregation data or clearly unaffected carriers within informative families were identified for this variant, so BS4 could not be assessed.	cspec
BP1	N/A	BP1 in this RASopathy framework is intended for truncating variants in genes without an established loss-of-function disease mechanism, and this variant is missense.	cspec
BP2	Not assessed	No phase data or point-based evidence were identified to determine whether BP2 applies.	cspec
BP3	N/A	BP3 is not applicable in the PTPN11 RASopathy specification.	cspec
BP4	Not met	BP4 requires REVEL at or below 0.3 for missense variants, but the REVEL score is 0.668. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the BayesDel score of 0.00798395 does not change the unmet REVEL threshold in this framework.	revel bayesdel spliceai cspec
BP5	Not assessed	No alternate molecular diagnosis or point-based evidence was identified to support BP5.	cspec
BP6	N/A	BP6 is not applicable in this specification and was not used.	cspec
BP7	N/A	BP7 applies to synonymous, intronic, or non-coding variants without predicted splice impact, but this variant is missense.	cspec

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