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.1 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%.2 The affected Lys70 residue falls within the PTPN11 critical N-SH2/PTP interaction region explicitly designated by the RASopathy specification for PM1.3 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 0.00.4
Final classification
VUS
PM1PP5
PTPN11
c.209A>G
p.Lys70Arg
This variant
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.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM1PP5
VUS
PTPN11 c.209A>G
PM1 + PP5
→
VUS
3
cspec ↗
4
revelbayesdelspliceai ↗cspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_001330437.1 · variants mapped to exon structure
PTPN11
NM_001330437.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PM1
moderate
Pathogenic
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.
PTPN11 PM1 residue list includes AA 69-77Variant affects Lys70
Assessed · not applied
· 7 not met · 10 not assessed
Pathogenic
PS1
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.
PS2
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.
PS3
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.
PS4
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.
PM2
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.
PM5
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.
PM6
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.
PP1
No informative segregation data were identified for this variant, so PP1 could not be assessed.
PP2
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.
PP3
PP3 requires REVEL at or above 0.7 for missense variants, but the REVEL score is 0.668.
Benign
BA1
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.
BS1
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.
BS2
No evidence was identified showing this variant in unaffected individuals at a level that would satisfy BS2.
BS4
No non-segregation data or clearly unaffected carriers within informative families were identified for this variant, so BS4 could not be assessed.
BP2
No phase data or point-based evidence were identified to determine whether BP2 applies.
BP4
BP4 requires REVEL at or below 0.3 for missense variants, but the REVEL score is 0.668.
BP5
No alternate molecular diagnosis or point-based evidence was identified to support BP5.
N/A · 9
PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.23942e-06; MAF= 0.00012%, 2/1613656 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33269e-05; MAF= 0.00133%, 1/75036 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,613,656
0 hom
0 hom
African/African American 1 / 75,036 |
0.0013% |
European (non-Finnish) 1 / 1,179,580 |
8.5e-05% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.668. BayesDel score = 0.00798395.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTPN11, a protein tyrosine phosphatase, is altered in various solid and hematologic malignancies.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links