LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-17
Case ID: NM_002834.4_c.169C_A_20260717_204540
Framework: ACMG/AMP 2015
Variant classification summary

NM_002834.4:c.169C>A

PTPN11  · NP_002825.3:p.(Gln57Lys)  · NM_002834.4
GRCh37: chr12:112888153 C>A  ·  GRCh38: chr12:112450349 C>A
Gene: PTPN11 Transcript: NM_002834.4
Final call
VUS
PM2 supporting PP2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PTPN11
Transcript
NM_002834.4
Protein
NP_002825.3:p.(Gln57Lys)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_002834.4:c.169C>A (p.Gln57Lys) is a missense variant in PTPN11, a gene associated with autosomal dominant RASopathies.
2
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.
3
REVEL in silico prediction score is 0.709, meeting the VCEP PP3 threshold of >=0.7 at Supporting strength.
4
PTPN11 has a missense z-score well above 3.09 in gnomAD, satisfying PP2 at Supporting strength under the VCEP rule.
5
The variant is absent from ClinVar with no prior classifications, and no publications describe this specific variant.
6
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).
7
No functional studies have tested p.Gln57Lys in any VCEP-approved assay (SHP-2 Phosphatase Activity, MEK Activation, ERK Activation).
8
No de novo, segregation, proband-count, or case-control data are available for this variant.
9
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.
10
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.
11
Final classification: Variant of Uncertain Significance (VUS).
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 PVS1 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.
cspec
PS1 Not met 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.
clinvar
PS2 Not met No de novo occurrence with confirmed maternity and paternity was identified for this variant in any reviewed source.
PS3 Not met 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.
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 Not met 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.
clinvar
PS5 N/A PS5 is not a recognized criterion in the ACMG/AMP 2015 framework or the RASopathy VCEP v2.3.0 specifications.
PM1 Not met 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.
cspec
PM2 Met 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).
gnomad_v2 gnomad_v4 cspec
PM3 N/A PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. RASopathies are autosomal dominant disorders; PM3 is not applicable.
PM4 N/A PM4 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.
PM5 Not met 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.
pm5_candidates clinvar
PM6 Not met No assumed de novo occurrence (without confirmation of paternity and maternity) was identified for this variant in any reviewed source.
PP1 Not met No co-segregation data are available for this variant. No family studies or informative meioses have been reported.
PP2 Met 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.
cspec
PP3 Met 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.
revel spliceai cspec
PP4 N/A PP4 is not applicable under the RASopathy VCEP v2.3.0; phenotypic specificity is addressed via PS4.
cspec
PP5 N/A PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
cspec
BA1 Not met 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.
gnomad_v2 gnomad_v4 cspec
BS1 Not met 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.
gnomad_v2 gnomad_v4 cspec
BS2 Not met 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.
gnomad_v2 gnomad_v4
BS3 N/A BS3 is not applicable under the RASopathy VCEP v2.3.0 for PTPN11.
cspec
BS4 Not met 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.
BP1 N/A BP1 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.
cspec
BP2 Not met 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.
BP3 N/A BP3 applies to in-frame deletions/insertions in a repetitive region without known function. This is a missense substitution; BP3 is not applicable.
BP4 Not met 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.
revel cspec
BP5 Not met No alternative molecular cause of RASopathy in a different gene has been identified for any proband carrying this variant. No proband data are available.
BP6 N/A BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
cspec
BP7 N/A BP7 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.
cspec
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