Variant classification summary

NM_002834.5:c.226G>A

PTPN11 · NP_002825.3:p.(Glu76Lys) · NM_002834.5

GRCh37: chr12:112888210 G>A · GRCh38: chr12:112450406 G>A

Gene: PTPN11 Transcript: NM_002834.5

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

PTPN11

Transcript

NM_002834.5

Protein

NP_002825.3:p.(Glu76Lys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: one VCEP-approved SHP-2 phosphatase assay supports a damaging effect for E76K.

2

PM1 moderate: residue 76 lies within the VCEP-approved directly interacting amino-acid interval 69-77.

3

PM2 supporting: the variant is absent from the evaluated gnomAD datasets.

4

PP3 supporting: REVEL 0.863 exceeds the VCEP threshold of 0.7.

Final determination: Under the PTPN11 VCEP Version 2.3 framework, one moderate criterion plus three supporting criteria satisfies no pathogenic or benign rule, so the variant is classified as VUS.

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	Not applicable: c.226G>A is a missense p.(Glu76Lys) variant, whereas the VCEP PVS1 rule is marked not applicable for RASopathy-specific assessment.	cspec pvs1_variant_assessment
PS1	Not met	Not met: no independently reported nucleotide change producing the same pathogenic p.Glu76Lys amino acid substitution is documented.	cspec PMID:14644997 clinvar
PS2	Not assessed	Not assessed: no documented proband-parent testing or de novo point count is available to apply the VCEP PS2 thresholds.	cspec
PS3	Met	Met, supporting: E76K is listed in the approved PTPN11 SHP-2 phosphatase assay's P/LP/VUS validation controls, satisfying the VCEP one-approved-assay rule.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:14644997
PS4	Not assessed	Not assessed: E76K was reported in 3 JMML and 1 AML specimens, but no germline RASopathy case-control counts, OR/RR, confidence interval, or PS4 point score were reported.	cspec PMID:14644997
PM1	Met	Met at Moderate: residue 76 falls within the VCEP-approved directly interacting N-SH2/PTPN domain interval of amino acids 69-77.	cspec
PM2	Met	Met at Supporting: the variant was absent from all-comers gnomAD v2.1 and v4.1 and from the available non-cancer subsets.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTPN11 VCEP explicitly marks PM3 as not applicable.	cspec
PM4	N/A	Not applicable: p.(Glu76Lys) is a missense substitution with no protein-length change, in-frame indel, or stop-loss consequence.	cspec pvs1_variant_assessment
PM5	Not met	Not met: the comparator collection contains 0 same-residue candidates, below the VCEP requirement of 1 likely pathogenic change at codon 76.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no apparently de novo occurrence without parental testing or VCEP PM6 point assignment is documented.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, so none of the VCEP PP1 thresholds can be applied.	cspec
PP2	Not assessed	Not assessed: the required PTPN11 gnomAD missense z score is unavailable, so comparison with the >3.09 threshold is impossible.	cspec
PP3	Met	Met (Supporting): REVEL score 0.863 meets the VCEP PP3 missense threshold of >= 0.7.	cspec revel
PP4	N/A	Not applicable: the PTPN11 VCEP explicitly directs phenotype-specific evidence to PS4 instead of using PP4 independently.	cspec
PP5	N/A	Not applicable: the PTPN11 VCEP prohibits PP5 use, regardless of pathogenic classifications reported by reputable sources.	cspec
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than reaching the VCEP's 0.05% filtering allele-frequency threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than reaching the VCEP's 0.025% filtering allele-frequency threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying healthy homozygote or heterozygote observation and no VCEP BS2 point assignment are documented.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the PTPN11 VCEP Version 2.3 explicitly marks BS3 as not applicable.	cspec
BS4	Not assessed	Not assessed: no non-segregating carrier or informative meiosis is documented to meet the VCEP BS4 requirement.	cspec
BP1	N/A	Not applicable: BP1 is restricted to named truncating variant types, whereas this variant is the missense substitution p.Glu76Lys.	cspec
BP2	Not assessed	Not assessed: no qualifying second pathogenic variant, cis/trans phase, and phenotype evidence is documented for the BP2 point thresholds.	cspec
BP3	N/A	Not applicable: the VCEP marks BP3 not applicable because no known benign repetitive areas exist in RASopathy genes.	cspec
BP4	Not met	Not met: REVEL score 0.863 exceeds the VCEP BP4 missense threshold of <= 0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternate-gene causative variant, fully explanatory alternate diagnosis, or VCEP BP5 point score is documented.	cspec
BP6	N/A	Not applicable: the PTPN11 VCEP prohibits BP6 use, regardless of benign classifications reported by reputable sources.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous, intronic, or non-coding variants, whereas this variant is missense p.(Glu76Lys).	cspec

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