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
PTPN11
Final classification
VUS
PTPN11 c.209A>G · p.Lys70Arg
PTPN11
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 ↗
Gene diagram
· NM_001330437.1 · variants mapped to exon structure
PTPN11
NM_001330437.1
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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