NM_001330437.1:c.1542G>C

PTPN11 · NP_001317366.1:p.(Gln514His) · NM_001330437.1

GRCh37: chr12:112926910 G>C · GRCh38: chr12:112489106 G>C

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Likely Pathogenic

PS1 strong PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Gln514His)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PTPN11 c.1542G>C (p.Gln514His) variant has been observed in somatic cancers in COSMIC (8 occurrences) and has been reported in ClinVar as pathogenic, including review by the ClinGen RASopathy Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls.

ClinVar also documents a different nucleotide change producing the same amino acid substitution, supporting PS1, and in silico results support a deleterious missense effect with REVEL 0.94 above the RASopathy VCEP PP3 threshold of 0.7, BayesDel 0.563665, and no predicted splice impact by SpliceAI (max delta score 0.00).

Final determination: Rule12 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 Likely Pathogenic.

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	This is a missense variant, and the reviewed PVS1 scaffold states that it does not fall into the null-variant categories used for PVS1. The PTPN11 RASopathy specification also lists PVS1 as not applicable for this context.	cspec pvs1_variant_assessment pvs1_gene_context
PS1	Met	ClinVar shows that the same amino acid substitution in PTPN11, p.Gln510His corresponding to this transcript's p.Gln514His, has also been established as pathogenic from a different nucleotide change. SpliceAI predicts no splice effect for this variant (max delta score 0.00), supporting interpretation at the protein level rather than through altered splicing.	clinvar spliceai cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant in the reviewed evidence, so PS2 was not applied.
PS3	Not assessed	RASopathy VCEP-approved functional assay frameworks for PTPN11 were reviewed, but no variant-specific approved functional result for p.(Gln514His) was identified in the reviewed materials. Therefore PS3 was not applied.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	This variant has been reported in ClinVar and is classified there as pathogenic by an expert panel, but the reviewed sources did not provide the point-based affected-proband counts required to apply the RASopathy VCEP PS4 rule for this exact variant. PS4 was therefore not applied.	clinvar
PM1	Not met	The PTPN11 RASopathy specification restricts PM1 to listed critical residues in the N-SH2/PTP interaction interface, and residue 514 is not included in that list. Cancer Hotspots also did not identify this residue as a statistically significant hotspot in the reviewed result.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, satisfying the PTPN11 RASopathy PM2 requirement that the variant be absent from population controls.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the reviewed PTPN11 RASopathy framework for this variant context.	cspec
PM4	N/A	This is a missense variant and does not alter protein length. PM4 is intended for in-frame insertions/deletions or stop-loss variants and was not applicable here.	cspec
PM5	Not assessed	Other pathogenic missense changes have been reported at the homologous canonical residue, including Gln510Arg and Gln510Glu, which corresponds to this transcript region. However, stronger same-amino-acid evidence supports PS1 for this variant, so PM5 was not applied separately to avoid double counting codon-based evidence.	clinvar PMID:15889278 PMID:15948193 PMID:16733669 cspec
PM6	Not assessed	No presumed de novo report without full parental confirmation was identified for this variant in the reviewed evidence, so PM6 was not applied.
PP1	Not assessed	No segregation data with informative meioses were identified for this variant, so PP1 was not applied.
PP2	Not assessed	The PTPN11 RASopathy framework allows PP2 when the gnomAD missense z score is greater than 3.09, but a gene-level missense z score was not documented in the reviewed case materials. PP2 was therefore not applied.	cspec
PP3	Met	For missense variants, the PTPN11 RASopathy specification supports PP3 when REVEL is at least 0.7. This variant has REVEL 0.94, which is above the 0.7 threshold; BayesDel is 0.563665, also supporting a deleterious effect, and SpliceAI predicts no significant splice impact with a max delta score of 0.00.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is listed as not applicable in the reviewed PTPN11 RASopathy framework and was not applied.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and is therefore well below the BA1 stand-alone benign threshold of 0.05% population frequency.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet the BS1 benign strong threshold of 0.025% population frequency.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in a sufficient number of unaffected individuals, so BS2 was not applied.
BS3	N/A	BS3 is listed as not applicable in the reviewed PTPN11 RASopathy framework for this case and was not applied.	cspec
BS4	Not assessed	No nonsegregation data were identified for this variant, so BS4 was not applied.
BP1	N/A	In the PTPN11 RASopathy specification, BP1 is used for truncating variants in genes where loss of function is not the established disease mechanism. This variant is missense, so BP1 is not applicable.	cspec
BP2	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant for a fully explained phenotype or in a context that would support BP2, so BP2 was not applied.
BP3	N/A	BP3 is listed as not applicable in the reviewed PTPN11 RASopathy framework and was not applied.	cspec
BP4	Not met	The PTPN11 RASopathy specification supports BP4 for missense variants only when REVEL is 0.3 or lower. This variant has REVEL 0.94, which is above the benign threshold, so BP4 is not met.	cspec revel
BP5	Not assessed	No evidence was identified for an alternate molecular explanation that would account for the phenotype independently of this variant, so BP5 was not applied.
BP6	N/A	BP6 is listed as not applicable in the reviewed PTPN11 RASopathy framework and was not applied.	cspec
BP7	N/A	This is a missense variant rather than a synonymous or qualifying intronic/non-coding change, so BP7 is not applicable.	cspec

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