Variant classification summary

NM_000314.8:c.209T>G

PTEN · NP_000305.3:p.(Leu70Arg) · NM_000314.8

GRCh37: chr10:89685314 T>G · GRCh38: chr10:87925557 T>G

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 moderate PM2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Leu70Arg)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Moderate): Mighell 2018 saturation-mutagenesis cumulative fitness score -4.645 for p.Leu70Arg is far below the -1.11 threshold, indicating severe loss of lipid phosphatase activity.

2

PM2 (Supporting): variant is entirely absent (AF = 0) from gnomAD v2.1, v4.1, and gnomAD-Canada.

3

PP3 (Supporting): REVEL 0.985 exceeds the VCEP cutoff of 0.7, predicting a deleterious missense effect.

4

Overall: VUS - the combination of 1 Moderate (PS3) and 2 Supporting (PM2, PP3) criteria meets no PTEN VCEP Pathogenic/Likely Pathogenic rule, and no benign rule applies.

Final determination: Under the ClinGen PTEN VCEP v3.2 criteria-combination rules, no combination rule matched the adjudicated criteria (PS3 moderate + PM2 supporting + PP3 supporting; no Very Strong, Strong, or benign criterion), so the variant is classified as Variant of Uncertain Significance.

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.209T>G is a missense substitution (p.Leu70Arg), not a null variant class to which PVS1 applies.	cspec vcep_pvs1_decisiontree_pten spliceai clinvar
PS1	Not assessed	Not assessed: insufficient evidence was available to determine whether p.Leu70Arg matches a known pathogenic variant at the same residue.
PS2	Not assessed	Not assessed: no confirmed or assumed de novo occurrence, parental testing, or family history data was documented.	clinvar cspec
PS3	Met	Met (Moderate): Mighell 2018 saturation-mutagenesis assay gives cumulative fitness score -4.645, far below the -1.11 PS3_Moderate threshold, indicating severe loss of lipid phosphatase activity.	PMID:29706350 vcep_mmc2 cspec
PS4	Not assessed	Not assessed: no case-control study or proband phenotype/specificity scores were available.	cspec clinvar PMID:29706350 PMID:17392385 PMID:25394175 PMID:25645574 PMID:28492532 PMID:20301661
PM1	Not assessed	Not assessed: insufficient evidence was available to evaluate whether Leu70 lies in a PM1-defined mutational hotspot.
PM2	Met	Met (Supporting): variant is entirely absent (AF = 0) from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	Not applicable: PM3 requires biallelic observations, but PTEN hamartoma tumor syndrome is autosomal dominant.	cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	Not applicable: missense substitution causes no protein length change, so the in-frame indel/stop-loss rule cannot apply.	cspec clinvar
PM5	Not assessed	Not assessed: insufficient evidence was available to determine whether a known pathogenic variant alters the same residue.
PM6	Not assessed	Not assessed: no assumed de novo occurrence or parental testing data was documented.	clinvar cspec
PP1	Not assessed	Not assessed: no co-segregation or meiosis data was available.	clinvar cspec
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate the gene's missense variation burden.
PP3	Met	Met (Supporting): REVEL score 0.985 exceeds the VCEP cutoff of 0.7, strongly predicting a deleterious missense effect.	revel cspec spliceai
PP4	N/A	Not applicable: phenotype specificity is already captured by PS4 under the PTEN VCEP, so PP4 would double-count.	cspec
PP5	N/A	Not applicable: no ClinGen expert-panel classification exists for this variant (ClinVar has zero expert-panel submissions).	cspec clinvar
BA1	Not met	Not met: allele frequency is 0 in gnomAD, far below the >0.056% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	Not met: allele frequency is 0 in gnomAD, below even the lowest 0.00043% BS1 band.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	Not met: no homozygous observations exist - the variant is absent from gnomAD.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS3	Not met	Not met: functional data show the opposite - a fitness score of -4.645 indicates severely reduced phosphatase activity, not >0 as BS3 requires.	PMID:29706350 vcep_mmc2 cspec
BS4	Not assessed	Not assessed: no family data demonstrating lack of segregation was available.	clinvar cspec
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate the variant's frequency in affected individuals.
BP2	Not met	Not met: no trans or cis observations with a pathogenic PTEN variant were documented.	cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada
BP3	N/A	Not applicable: the PTEN VCEP declares BP3 inapplicable, and the variant is a missense substitution, not an in-frame indel.	cspec
BP4	Not met	Not met: REVEL 0.985 is above the <0.5 BP4 threshold.	revel cspec
BP5	Not assessed	Not assessed: no cases with an alternate molecular basis for disease were documented.	cspec clinvar PMID:29706350 PMID:17392385 PMID:25394175 PMID:25645574 PMID:28492532
BP6	N/A	Not applicable: no ClinGen expert-panel classification exists, and no submission labels the variant benign.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants; c.209T>G is a missense substitution.	cspec spliceai

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