Variant classification summary

NM_000314.8:c.238A>G

PTEN · NP_000305.3:p.(Lys80Glu) · NM_000314.8

GRCh37: chr10:89690831 A>G · GRCh38: chr10:87931074 A>G

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 moderate PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Lys80Glu)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PTEN c.238A>G (p.Lys80Glu) is a missense variant in exon 4 of the phosphatase domain.

2

The variant is absent from population databases (gnomAD v2.1 and v4.1), meeting PM2_Supporting per PTEN VCEP.

3

Functional data from Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis assay demonstrates a cumulative fitness score of -1.60681967, below the -1.11 threshold for PS3_Moderate, indicating significantly reduced phosphatase activity with high confidence.

4

Computational evidence supports pathogenicity: REVEL score 0.775 (>0.7 threshold for PP3) per PTEN VCEP specification.

5

PP2 is applied as PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism.

6

No benign criteria are met: variant is absent from population databases (BA1/BS1 not met), no homozygous observations (BS2 not met), functional data shows damaging effect (BS3 not met), REVEL exceeds benign threshold (BP4 not met).

7

Under the PTEN VCEP v3.2.0 combination rules, this evidence set (PS3_Moderate + PM2_Supporting + PP2 + PP3 = 1 moderate + 3 supporting) does not trigger any Pathogenic or Likely Pathogenic classification rule. The variant is classified as Variant of Uncertain Significance (VUS).

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v3.2.0 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 to missense variants. The PTEN VCEP PVS1 decision tree applies only to nonsense, frameshift, canonical ±1,2 splice site disruptions, and CNVs. NM_000314.8:c.238A>G (p.Lys80Glu) is a missense substitution in exon 4 and does not fall into any null-variant bucket.	vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	Not met	PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change, or a different variant at the same nucleotide position as a known pathogenic splicing variant. No other nucleotide change resulting in p.Lys80Glu has been identified as a previously established pathogenic variant, nor is there a known pathogenic splicing variant at c.238.	cspec
PS2	Not met	PS2 requires a de novo observation with both maternity and paternity confirmed in a patient with the disease and no family history. No published de novo case of PTEN c.238A>G with confirmed parentage was identified in indexed literature or clinical databases.
PS3	Met	PS3_Moderate is met per PTEN VCEP specification. The variant p.Lys80Glu (K80E) was directly assayed in the Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional study of PTEN phosphatase activity. The cumulative fitness score (Cum_score) from Table S2 of the study is -1.60681967, which is ≤ -1.11, meeting the VCEP threshold for PS3_Moderate. The measurement is flagged as high confidence (High_conf=True).	vcep_mmc2 PMID:29706350
PS4	Not assessed	PS4 requires proband counts with specificity scores per PTEN VCEP thresholds. The ClinVar record (variation ID 571869) shows a single clinical laboratory submission classified as Pathogenic (review status: criteria provided, single submitter). The submission audit found 0 usable submissions and 0 criterion-lead submissions. Exact proband counts with phenotype specificity scores are not available from the current evidence. PS4 cannot be applied without quantified proband data.	clinvar
PS5	N/A	PS5 applies when a reputable source recently reports a variant as pathogenic but the evidence is not available for independent evaluation. This variant is being directly evaluated through the PTEN VCEP framework; its classification is being determined here rather than adopted from an external source.
PM1	Not met	The PTEN VCEP defines PM1 as located in a mutational hot spot and/or critical functional domain, specifically residues in catalytic motifs: 90-94, 123-130, and 166-168 (NP_000305.3). The variant p.Lys80Glu is at position 80, which lies outside all three defined catalytic motif ranges. Although residue 80 is within the broader phosphatase domain (residues 7-185), the VCEP specification restricts PM1 to the enumerated catalytic motifs.	cspec
PM2	Met	PM2_Supporting is met per PTEN VCEP specification. The variant is absent from gnomAD v2.1 and v4.1 (allele frequency < 0.00001 / 0.001%), meeting the VCEP threshold for population absence. Absent also in gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4
PM5	Not met	PM5 requires a missense change at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic, with the interrogated variant having a BLOSUM62 score equal to or less than the known variant. No different missense change at PTEN residue 80 (Lys) has been established as pathogenic or likely pathogenic in ClinVar or the literature.	pm5_candidates
PM6	Not met	PM6 requires an assumed de novo occurrence (without confirmation of paternity and maternity) in a proband with the disease and no family history. No de novo reports, confirmed or unconfirmed, were identified for PTEN c.238A>G in the literature or clinical databases.
PP1	Not met	PP1 requires co-segregation with disease in multiple affected family members with ≥3 meioses (PTEN VCEP: 3-4 meioses = Supporting, 5-6 = Moderate, ≥7 across ≥2 families = Strong). No co-segregation data or family studies involving PTEN c.238A>G were identified.
PP2	Met	PP2 is met per PTEN VCEP specification. PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PTEN. The variant p.Lys80Glu is a missense substitution.	cspec
PP3	Met	PP3 is met per PTEN VCEP specification for missense variants. The REVEL score for this variant is 0.775, which exceeds the VCEP threshold of >0.7 for multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for this missense variant and does not contradict the REVEL-based PP3 call.	revel spliceai bayesdel
PP4	N/A	PP4 is designated as Not Applicable by the PTEN VCEP. Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2.	cspec
PP5	N/A	PP5 is designated as Not Applicable by the PTEN VCEP. This criterion is not used in the PTEN expert panel specification.	cspec
BA1	Not met	BA1 requires a gnomAD filtering allele frequency >0.00056 (0.056%) per PTEN VCEP. The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0.0, which does not meet the BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires a gnomAD filtering allele frequency of ≥0.0000043 (0.00043%) for Supporting or ≥0.000043 (0.0043%) for Strong per PTEN VCEP. The variant is absent from gnomAD v2.1 and v4.1 (AF = 0.0), which does not meet either BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual (Strong for one confirmed homozygous, Supporting for two unconfirmed or if BS1 also applied). No homozygous observations of PTEN c.238A>G were identified in gnomAD or any other source.	gnomad_v2 gnomad_v4
BS3	Not met	BS3_Supporting per PTEN VCEP requires phosphatase activity >0 in the Mighell et al. 2018 assay (PMID: 29706350). The variant K80E has a cumulative fitness score (Cum_score) of -1.60681967, which is well below 0, indicating damaging effect on phosphatase activity. BS3 is not met. BS3_Strong for splicing assays showing no impact is not applicable as this is not a splicing variant.	vcep_mmc2 PMID:29706350
BS4	Not met	BS4 requires lack of segregation in affected members of one family (Supporting) or two or more families (Strong) per PTEN VCEP. No segregation data, positive or negative, were identified for PTEN c.238A>G.
BP1	N/A	BP1 is designated as Not Applicable by the PTEN VCEP. This criterion (missense variant in a gene where primarily truncating variants cause disease) does not apply to PTEN under the expert panel specification.	cspec
BP2	Not met	BP2 requires observation in trans with a pathogenic or likely pathogenic PTEN variant or at least three observations in cis/phase unknown with different P/LP PTEN variants per the VCEP specification. No such observations were identified for PTEN c.238A>G.
BP4	Not met	BP4 for missense variants per PTEN VCEP requires REVEL score <0.5. The REVEL score for PTEN c.238A>G is 0.775, which exceeds the benign threshold and is instead consistent with a deleterious prediction (supporting PP3). BP4 is not met.	revel
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease, where the other gene/disorder is highly penetrant and the patient's personal/family history shows no overlap with PTEN. No such case has been reported for PTEN c.238A>G.
BP6	N/A	BP6 is designated as Not Applicable by the PTEN VCEP. This criterion (reputable source classifies as benign) is not used in the PTEN expert panel specification.	cspec
BP7	N/A	BP7 applies only to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no splice impact. NM_000314.8:c.238A>G is a missense variant (p.Lys80Glu), not a synonymous or intronic variant. BP7 is not applicable.	cspec

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