Variant classification summary

NM_000314.8:c.389G>A

PTEN · NP_000305.3:p.(Arg130Gln) · NM_000314.8

GRCh37: chr10:89692905 G>A · GRCh38: chr10:87933148 G>A

Gene: PTEN Transcript: NM_000314.8

Final call

Pathogenic

PS1 strong PS3 moderate PM1 moderate PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Arg130Gln)

gnomAD AF

1.239244903295524e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS1 Strong is supported by the PTEN Expert Panel's Pathogenic classification of p.Arg130Gln.

2

Pathogenic: PS3 Moderate is supported by the high-confidence phosphatase score of -2.04016411.

3

Pathogenic: PM1 Moderate is supported because Arg130 lies in the VCEP-defined catalytic-motif interval 123-130.

4

Pathogenic: PM2 Supporting is supported by gnomAD v4.1 allele frequency of 1.23924e-06.

5

Pathogenic: PP2 Supporting applies to this PTEN missense variant under the VCEP rule.

6

Pathogenic: PP3 Supporting is supported by the REVEL score of 0.976.

Final determination: Under the PTEN VCEP v3.2 framework, Rule7 is satisfied by one Strong pathogenic criterion, two Moderate pathogenic criteria, and at least two Supporting pathogenic criteria, producing a Pathogenic call.

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: p.Arg130Gln is a missense substitution, whereas the PTEN PVS1 decision tree has no missense path and assigns PVS1 only to specified loss-of-function variant classes.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	Met	Met at Strong: the exact p.Arg130Gln variant is recorded as Pathogenic by the PTEN Expert Panel, satisfying the same-amino-acid-change rule.	cspec clinvar
PS2	Not assessed	Not assessed: de novo claims lack a verified primary case report documenting phenotype, no family history, and confirmed maternity and paternity.	clinvar
PS3	Met	Met at Moderate: the high-confidence PTEN phosphatase assay score is -2.04016411, below the VCEP PS3 threshold of ≤ -1.11.	cspec vcep_mmc2 PMID:29706350 PMID:32350270
PS4	Not assessed	Not assessed: no variant-specific case-control counts or odds ratio, and no Cleveland Clinic or pediatric phenotype-specificity scores, are available for the PS4 rule.	cspec gnomad_v4 PMID:32350270 PMID:28572459
PM1	Met	Met at Moderate: p.Arg130Gln is residue 130, within the VCEP-defined catalytic-motif interval 123-130.	cspec
PM2	Met	Met at Supporting: gnomAD v4.1 total AF 1.23924e-06 and highest subpopulation AF 1.69511e-06 are below the PTEN VCEP PM2 thresholds.	cspec gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP specification explicitly marks PM3 as not applicable.	cspec
PM4	N/A	Not applicable: p.Arg130Gln changes one amino acid without altering protein length, so it does not meet the PTEN VCEP PM4 insertion/deletion or stop-loss rule.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: zero same-residue comparator candidates and no qualifying BLOSUM62 comparison are available.	cspec pm5_candidates
PM6	Not assessed	Not assessed: reported de novo observations lack verified counts, proband details, family-history status, and parental-testing status for the VCEP thresholds.	clinvar
PP1	Not assessed	Not assessed: no verified affected relatives, cosegregation observations, or informative meiosis count are available.
PP2	Met	Met at Supporting: the VCEP marks PP2 applicable for this missense PTEN variant under its low-benign-missense and common-missense-mechanism rule.	cspec
PP3	Met	Met: missense REVEL score 0.976 exceeds the PTEN VCEP PP3 cutoff of >0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 rather than permitting PP4.	cspec
PP5	Met	Not applicable: the PTEN VCEP explicitly prohibits PP5 use regardless of available pathogenic assertions.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 total allele frequency is 1.23924e-06, below the PTEN VCEP BA1 threshold of >0.00056.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 total allele frequency is 1.23924e-06, below the PTEN VCEP BS1 Supporting lower boundary of 0.0000043.	cspec gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes among 1,613,886 alleles, so the required homozygous observation is absent.	cspec gnomad_v4
BS3	Not met	Not met: the high-confidence phosphatase score is -2.04016411, not greater than the VCEP BS3_Supporting requirement of > 0.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected family members with documented non-segregation are reported for this variant.
BP1	N/A	Not applicable: the PTEN VCEP explicitly excludes BP1 for PTEN.	cspec
BP2	Not assessed	Not assessed: no documented trans observation or at least three cis/phase-unknown observations with different pathogenic PTEN variants are available.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly marks BP3 as Not Applicable, regardless of the variant's missense consequence or repeat-region context.	cspec
BP4	Not met	Not met: missense REVEL score 0.976 is above, not below, the PTEN VCEP BP4 cutoff of <0.5.	cspec revel
BP5	Not assessed	Not assessed: no two cases with an alternate highly penetrant molecular basis and non-overlapping PTEN history are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits BP6 use regardless of any reputable benign-source assertion.	cspec
BP7	N/A	Not applicable: c.389G>A is a missense exonic variant, outside BP7's synonymous or intronic +7/-21 scope.	cspec

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