Variant classification summary

NM_001330437.1:c.1052G>A

PTPN11 · NP_001317366.1:p.(Arg351Gln) · NM_001330437.1

GRCh37: chr12:112915779 G>A · GRCh38: chr12:112477975 G>A

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Benign

BA1 stand-alone benign BP6 supporting benign

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Arg351Gln)

gnomAD AF

0.0004255386842502963 (v2.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTPN11 c.1052G>A (p.Arg351Gln) variant has been observed in somatic cancers in COSMIC and is reported in ClinVar with an expert-panel benign classification.

2

In population data, this variant is present in gnomAD v2.1 with overall AF 0.04255% (107/251446), South Asian AF 0.34303% (105/30610), and grpmax FAF 0.28984%, which is above the PTPN11 VCEP BA1 threshold of 0.05%; it was not observed in gnomAD v4.1.

3

Available computational evidence does not meet the PTPN11 VCEP PP3 threshold because REVEL is 0.516, below the required 0.7, while SpliceAI predicts no significant splice impact with a max delta score of 0.00.

Final determination: Rule17 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Benign.

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
PM5	Not met	Available reviewed sources did not identify a different pathogenic or likely pathogenic missense change at codon 351 in PTPN11, so the same-residue missense comparator requirement for PM5 is not met.	clinvar cspec
PS1	Not met	Available reviewed sources did not identify a previously established pathogenic PTPN11 variant with the same amino acid change, so PS1 is not met.	clinvar cspec
PP3	Not met	For PTPN11 missense variants, the VCEP PP3 threshold is REVEL at least 0.7. This variant has REVEL 0.516, BayesDel 0.0913187, and SpliceAI max delta score 0.00, so the computational evidence does not meet the PP3 threshold.	cspec revel bayesdel spliceai
PM4	N/A	This is a missense variant and does not change protein length, so PM4 is not applicable.	cspec
PM2	Not met	PM2 requires absence from gnomAD. This variant is present in gnomAD v2.1 with overall AF 0.04255% (107/251446), South Asian AF 0.34303% (105/30610), and grpmax FAF 0.28984%, so PM2 is not met.	cspec gnomad_v2 gnomad_v4
PS2	Not assessed	No confirmed de novo germline RASopathy observation with maternity and paternity confirmation was identified in the reviewed sources, so PS2 cannot be applied from the currently available evidence.	cspec PMID:14644997 PMID:15385933 PMID:15710330
PVS1	N/A	The PTPN11 RASopathy VCEP does not apply PVS1 in this framework, and this variant is a missense change rather than a null variant.	cspec pvs1_variant_assessment
BP7	N/A	BP7 is for synonymous or certain non-coding variants with no predicted splice impact. This variant is missense, so BP7 is not applicable.	cspec
PM1	Not met	For PTPN11, PM1 is limited to specific listed residues and residue ranges in the N-SH2/PTP interaction interface. Codon 351 is not included in that allowed list, so PM1 is not met.	cspec
BP1	N/A	In this VCEP framework, BP1 is used for truncating variants in genes where gain of function is the main RASopathy mechanism. This variant is missense, so BP1 is not applicable.	cspec
BP4	Not met	For PTPN11 missense variants, the VCEP BP4 threshold is REVEL 0.3 or lower. This variant has REVEL 0.516, so BP4 is not met, although SpliceAI predicts no significant splice impact with max delta score 0.00.	cspec revel spliceai bayesdel
BP3	N/A	The RASopathy VCEP indicates there are no known benign repetitive regions in these genes for BP3 use, so BP3 is not applicable.	cspec
PS3	Not assessed	The VCEP allows PS3 only when approved functional assays support a damaging effect. No exact p.(Arg351Gln) result from an approved assay was identified in the reviewed sources, so PS3 cannot be applied from the currently available evidence.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:15710330 PMID:19179468
PM3	N/A	PM3 is not applicable in this dominant RASopathy VCEP framework.	cspec
PP4	N/A	PP4 is not used in this VCEP framework because phenotype specificity is handled through PS4 and related point-based rules.	cspec
BS3	N/A	BS3 is not used in this VCEP framework.	cspec
PP5	N/A	PP5 is not used by this VCEP framework.	cspec
BP5	Not assessed	No evidence was identified showing a fully explanatory alternative molecular cause of a RASopathy or a non-RASopathy explanation in the same individual, so BP5 cannot be assessed from the current evidence.	cspec clinvar
BA1	Met	The PTPN11 VCEP BA1 threshold is gnomAD filtering allele frequency at least 0.05%. In gnomAD v2.1, this variant has grpmax FAF 0.28984% and highest observed population AF 0.34303% in South Asian samples (105/30610), which are above the 0.05% threshold, so BA1 is met.	cspec gnomad_v2 gnomad_v4
PP2	Not assessed	PP2 requires a gnomAD missense z score greater than 3.09. That gene-level missense constraint value was not identified in the reviewed sources, so PP2 was not assessed.	cspec
BS4	Not assessed	No informative family data showing lack of segregation were identified in the reviewed sources, so BS4 cannot be applied.	cspec PMID:14644997 PMID:15385933 PMID:19047918
PP1	Not assessed	No segregation data with informative meioses were identified for this variant, so PP1 cannot be applied.	cspec PMID:14644997 PMID:15385933 PMID:15710330
BS1	Not assessed	This variant exceeds the BS1 frequency threshold, but BA1 is already met and is the more appropriate stand-alone population criterion, so BS1 was not separately counted.	cspec gnomad_v2
BP2	Not assessed	No evidence was identified showing this variant with a qualifying alternative pathogenic variant in the same gene with the phase and phenotype context required for BP2, so BP2 cannot be applied.	cspec clinvar
BS2	Not assessed	Although the variant is present in population databases, no reviewed source documented phenotyped healthy individuals meeting the VCEP BS2 requirements, so BS2 was not applied.	cspec gnomad_v2 gnomad_v4
PM6	Not assessed	No assumed de novo germline RASopathy observation without maternity and paternity confirmation was identified in the reviewed sources, so PM6 cannot be applied.	cspec PMID:14644997 PMID:15385933 PMID:15710330
PS4	Not met	The available reports and cited publications concern somatic leukemia or JMML settings, and no de-duplicated germline RASopathy case enrichment versus controls was identified. Given the population frequency in gnomAD v2.1, the available evidence does not support PS4.	cspec clinvar gnomad_v2 PMID:14644997 PMID:15385933 PMID:19047918 PMID:19179468
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.