About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.169C>A, p.(Gln57Lys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen PTPN11 VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 and v4.1 population databases. Under the RASopathy VCEP v2.3.0, PM2 is applied at Supporting strength when the variant is absent from controls (gnomAD).
PP2Supporting
PP2 · supporting
PTPN11 has a missense z-score well above 3.09 in gnomAD (v2.1: z=5.68; v4.1: z=7.03), satisfying the RASopathy VCEP v2.3.0 rule that PP2 applies at Supporting strength when the gnomAD missense z-score exceeds 3.09.
PP3Supporting
PP3 · supporting
REVEL score of 0.709 meets the RASopathy VCEP v2.3.0 threshold of >=0.7 for PP3 at Supporting strength. SpliceAI predicts no significant splice impact (max delta = 0.03), consistent with a missense mechanism.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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: PM2 supporting, PP2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PTPN11 VCEP v2.3.0, with the data and sources behind each one.
29 criteria with recorded statuses: 3 met · 15 not met · 0 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002834.4:c.169C>A (p.Gln57Lys) is a missense variant in PTPN11, a gene associated with autosomal dominant RASopathies.
The variant is absent from gnomAD v2.1 and v4.1 population databases, satisfying PM2 at Supporting strength under the RASopathy VCEP v2.3.0.
REVEL in silico prediction score is 0.709, meeting the VCEP PP3 threshold of >=0.7 at Supporting strength.
PTPN11 has a missense z-score well above 3.09 in gnomAD, satisfying PP2 at Supporting strength under the VCEP rule.
The variant is absent from ClinVar with no prior classifications, and no publications describe this specific variant.
PM1 is not applicable: position 57 (Gln57) is adjacent to but not within the VCEP-defined functional domain residues (AA 58-63 are the closest listed range).
No functional studies have tested p.Gln57Lys in any VCEP-approved assay (SHP-2 Phosphatase Activity, MEK Activation, ERK Activation).
No de novo, segregation, proband-count, or case-control data are available for this variant.
Under the RASopathy VCEP v2.3.0 classification rules, three Supporting-level pathogenic criteria (PM2_Supporting, PP2, PP3) are met. No Strong, Very Strong, Moderate, or Stand-Alone criteria are met on either the pathogenic or benign side.
The VCEP classification framework requires at minimum either (a) one Strong criterion with >=2 Supportive, or (b) one Moderate criterion with >=4 Supportive, or (c) >=2 Moderate criteria to reach Likely Pathogenic. None of these thresholds are met. No benign criteria are triggered.
Final classification: Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PM2 SupportingThe variant is absent from gnomAD v2.1 and v4.1 population databases. Under the RASopathy VCEP v2.3.0, PM2 is applied at Supporting strength when the variant is absent from controls (gnomAD). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 exomes (AC=0).
- Absent from gnomAD v4.1 exomes (AC=0).
Sources
PP2 SupportingPTPN11 has a missense z-score well above 3.09 in gnomAD (v2.1: z=5.68; v4.1: z=7.03), satisfying the RASopathy VCEP v2.3.0 rule that PP2 applies at Supporting strength when the gnomAD missense z-score exceeds 3.09. Details ▾Hide ▴
Evidence considered
- PTPN11 gnomAD missense z-score >> 3.09 threshold (v2.1 ~5.68
- v4.1 ~7.03).
Still missing
- Exact z-score not captured in case evidence files
- verified from gnomAD gene constraint data. Human review recommended to confirm current gnomAD build values.
Sources
PP3 SupportingREVEL score of 0.709 meets the RASopathy VCEP v2.3.0 threshold of >=0.7 for PP3 at Supporting strength. SpliceAI predicts no significant splice impact (max delta = 0.03), consistent with a missense mechanism. Details ▾Hide ▴
Evidence considered
- REVEL score 0.709 >= 0.7 (VCEP threshold).
- SpliceAI max delta = 0.03 (no splice impact).
Sources
Not met · 15 · evaluated, threshold not reached
PS1 No previously established pathogenic variant at the same amino acid (Gln57) was identified in ClinVar or the literature. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no established pathogenic Q57 variant identified.
Sources
PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant in any reviewed source. Details ▾Hide ▴
Evidence considered
- No de novo evidence found
- no PubMed publications for this variant.
Still missing
- Absence of de novo data is not evidence of absence
- clinical testing may reveal de novo occurrences.
PS3 The variant p.Gln57Lys has not been tested in any VCEP-approved functional assay (SHP-2 Phosphatase Activity, MEK Activation, or ERK Activation). It is not listed among the validation controls in the RASopathy VCEP functional studies spreadsheet. Details ▾Hide ▴
Evidence considered
- Q57K not present in VCEP-approved assay validation control lists (SHP-2 Phosphatase: D61N
- Y63C
- A72S
- E76D
- E76K
- Q79R
- I282V
- N308D
- MEK/ERK PTPN11 columns: D61N
- N308D).
Still missing
- No variant-specific functional data available.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No proband or case-control data are available for this variant. The variant is absent from ClinVar with zero submissions, and no publications describe affected individuals carrying this variant. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar (0 submitters)
- no probands carrying this variant reported in literature.
Still missing
- Absence of proband data is not evidence of absence.
Sources
PM1 Under the RASopathy VCEP v2.3.0, PM1 is restricted to specific directly interacting residues between N-SH2 and PTPN domains: AA 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284. Position 57 (Gln57) is not included in this enumerated list. Details ▾Hide ▴
Evidence considered
- VCEP PM1 domain residues: AA 58-63 are the closest listed range
- position 57 is adjacent but not included.
Sources
PM5 No likely pathogenic or pathogenic variant at the same codon (Gln57) was identified in ClinVar. The PM5 candidate search found zero comparator variants at residue Q57. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants at codon Q57 found in ClinVar.
Sources
pm5_candidatesclinvar ↗
PM6 No assumed de novo occurrence (without confirmation of paternity and maternity) was identified for this variant in any reviewed source. Details ▾Hide ▴
Evidence considered
- No de novo reports found
- no PubMed publications for this variant.
Still missing
- Absence of de novo data is not evidence of absence.
PP1 No co-segregation data are available for this variant. No family studies or informative meioses have been reported. Details ▾Hide ▴
Evidence considered
- No segregation data available.
BA1 The variant is absent from gnomAD (allele frequency = 0%). The BA1 threshold under the RASopathy VCEP v2.3.0 is gnomAD filtering allele frequency >=0.05%, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- AF = 0.0%
- below 0.05% BA1 threshold.
Sources
BS1 The variant is absent from gnomAD. The BS1 threshold under the RASopathy VCEP v2.3.0 is gnomAD filtering allele frequency >=0.025%, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD
- AF = 0.0%
- below 0.025% BS1 threshold.
Sources
BS2 No healthy adult individuals have been reported to carry this variant. The variant is absent from population databases, and no clinical reports describe unaffected carriers. Details ▾Hide ▴
Evidence considered
- No healthy carriers identified
- variant absent from gnomAD.
Sources
BS4 No segregation data are available to demonstrate lack of segregation in affected family members. The VCEP requires at least one informative meiosis showing lack of segregation. Details ▾Hide ▴
Evidence considered
- No segregation data available.
BP2 No evidence of an alternative molecular cause of RASopathy in the same gene or in trans/cis with a pathogenic variant. No proband data are available to assess this criterion. Details ▾Hide ▴
Evidence considered
- No proband data available
- variant not observed in any clinical context.
BP4 REVEL score of 0.709 exceeds the RASopathy VCEP v2.3.0 BP4 threshold of <=0.3. The in silico prediction does not support a benign effect. SpliceAI predicts no splice impact, but BP4 requires REVEL <=0.3 for missense variants. Details ▾Hide ▴
BP5 No alternative molecular cause of RASopathy in a different gene has been identified for any proband carrying this variant. No proband data are available. Details ▾Hide ▴
Evidence considered
- No proband data available for BP5 assessment.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable under the ClinGen RASopathy VCEP v2.3.0 for PTPN11. Loss of function and/or haploinsufficiency has not been clearly identified as a disease mechanism for RASopathies, and this is a missense variant, not a null variant. Details ▾Hide ▴
Evidence considered
- VCEP rule: PVS1 applicability = Not Applicable
- missense variant at c.169C>A (p.Gln57Lys) does not fall into null-variant buckets.
Sources
PM3 VCEPPM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. RASopathies are autosomal dominant disorders; PM3 is not applicable. Details ▾Hide ▴
Evidence considered
- RASopathies are autosomal dominant
- PM3 applies only to recessive disorders.
PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. This is a missense substitution; PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- PM4 applies only to in-frame indels and stop-loss variants.
PP4 VCEPPP4 is not applicable under the RASopathy VCEP v2.3.0; phenotypic specificity is addressed via PS4. Details ▾Hide ▴
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS3 VCEPBS3 is not applicable under the RASopathy VCEP v2.3.0 for PTPN11. Details ▾Hide ▴
BP1 N/ABP1 under the RASopathy VCEP v2.3.0 applies only to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, or exon deletions) in genes where gain-of-function is the disease mechanism. This is a missense variant; BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- VCEP BP1 rule: applicable only to truncating LOF variants
- this is a missense variant.
Sources
BP3 VCEPBP3 applies to in-frame deletions/insertions in a repetitive region without known function. This is a missense substitution; BP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP3 applies only to in-frame indels in repetitive regions.
BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This is a missense variant (c.169C>A, p.Gln57Lys); BP7 is not applicable. Details ▾Hide ▴
PS5 N/APS5 is not a recognized criterion in the ACMG/AMP 2015 framework or the RASopathy VCEP v2.3.0 specifications. Details ▾Hide ▴
Evidence considered
- No corresponding ACMG/AMP or VCEP criterion.
Identifiers
- Gene
- PTPN11
- Transcript
- NM_002834.4
- Coding (HGVS c.)
- NM_002834.4:c.169C>A
- Protein (HGVS p.)
- NP_002825.3:p.(Gln57Lys)
- GRCh38
- chr12:112450349 C>A
- GRCh37
- chr12:112888153 C>A
Gene diagram
Every interpreted variant in PTPN11, mapped onto the exon structure of NM_002834.4. Select a row to find it on the plot.
PTPN11NM_002834.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PTPN11
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.709
- BayesDel
- 0.161
How the predictions were used
PP3 SupportingREVEL score of 0.709 meets the RASopathy VCEP v2.3.0 threshold of >=0.7 for PP3 at Supporting strength. SpliceAI predicts no significant splice impact (max delta = 0.03), consistent with a missense mechanism. Details ▾Hide ▴
Evidence considered
- REVEL score 0.709 >= 0.7 (VCEP threshold).
- SpliceAI max delta = 0.03 (no splice impact).
Sources
BP4 REVEL score of 0.709 exceeds the RASopathy VCEP v2.3.0 BP4 threshold of <=0.3. The in silico prediction does not support a benign effect. SpliceAI predicts no splice impact, but BP4 requires REVEL <=0.3 for missense variants. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This is a missense variant (c.169C>A, p.Gln57Lys); BP7 is not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.709. BayesDel score = 0.16136.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243113
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002834.4%3Ac.169C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112888153-C-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112450349-C-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-112450349-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002834.4%3Ac.169C…
- OncoKB ↗www.oncokb.org/gene/PTPN11/Q57K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTPN11+c.169C%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.709. BayesDel score = 0.16136.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.