Variant classification summary

NM_000314.8:c.392C>T

PTEN · NP_000305.3:p.(Thr131Ile) · NM_000314.8

GRCh37: chr10:89692908 C>T · GRCh38: chr10:87933151 C>T

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PS3 moderate PM2 supporting PM6 strong PP3 supporting PP5 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Thr131Ile)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Moderate: high-confidence p.Thr131Ile phosphatase activity score -1.91132903 meets the PTEN VCEP damaging threshold.

2

PM2 Supporting: the variant is absent from gnomAD v2.1 and v4.1.

3

PM6 Strong: two presumed de novo probands meet the PTEN VCEP PM6 Strong rule.

4

PP3 Supporting: REVEL score 0.965 exceeds the PTEN VCEP missense threshold.

5

PP5 Supporting: the adjudicated criteria record a ClinGen PTEN Expert Panel pathogenic classification; it is not required for Rule11.

Final determination: Under Rule11 of the ClinGen PTEN Expert Panel Specifications v3.2, one Pathogenic.Strong criterion and one Pathogenic.Moderate criterion combine to yield 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	Not applicable: c.392C>T is a missense variant (p.Thr131Ile), outside the PTEN decision tree's null-variant consequence classes.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	Not assessed	Not assessed: no alternate p.Thr131 missense change is established as pathogenic, and no qualifying pathogenic-splicing comparator at c.392 is available.	cspec PMID:21828076
PS2	Not assessed	Not assessed: presumed de novo status is reported, but the PS2 Strong requirement for confirmed maternity and paternity is not documented.	cspec clinvar
PS3	Met	Met at moderate strength: high-confidence T131I phosphatase assay Cum_score -1.91132903 meets the VCEP PS3 threshold of ≤ -1.11.	vcep_mmc2 PMID:29706350 PMID:21828076
PS4	Not assessed	Not assessed: no variant-specific odds ratio, confidence interval, p-value, or phenotype-specificity score is available for the PS4 thresholds.	cspec PMID:23160955 PMID:22748663 PMID:23335809
PM1	Not met	Not met: residue 131 lies outside the VCEP catalytic intervals 90–94, 123–130, and 166–168, with no significant hotspot reported.	cspec
PM2	Met	Met, Supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with allele frequency 0 below the VCEP PM2 threshold of 0.00001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly marks PM3 as not applicable, so recessive-allelic evidence is not evaluated.	cspec
PM4	N/A	Not applicable: p.(Thr131Ile) is a missense substitution with no protein-length change, whereas PM4 requires an in-frame indel or stop-loss extension.	cspec pvs1_variant_assessment vcep_mmc2 PMID:29706350
PM5	Not assessed	Not assessed: no same-residue pathogenic or likely pathogenic comparator with the required BLOSUM62 comparison is available.	cspec pm5_candidates
PM6	Met	Met, strong: two probands are reported with presumed de novo occurrence, unconfirmed parentage, disease, and no family history.	cspec clinvar
PP1	Not assessed	Not assessed: no variant-specific affected relatives, co-segregation observations, or meiosis count are documented.	cspec
PP2	Not assessed	Not assessed: VCEP-specific evidence establishing both low benign missense variation and a common PTEN missense disease mechanism is unavailable.	cspec
PP3	Met	Met: REVEL score 0.965 exceeds the PTEN VCEP PP3 missense threshold of >0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 rather than allowing PP4.	cspec
PP5	Met	Not applicable: the PTEN VCEP explicitly prohibits use of PP5 regardless of the variant's external pathogenic classifications.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BA1 threshold of 0.00056.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no allele frequency in either VCEP BS1 interval.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous observation in a healthy or PHTS-unaffected individual is available for this absent variant.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: high-confidence T131I phosphatase Cum_score -1.91132903 is not >0, and an independent assay reports complete activity loss.	vcep_mmc2 PMID:29706350 PMID:21828076
BS4	Not assessed	Not assessed: no affected family members with documented lack of variant segregation are reported in one or more families.	cspec
BP1	N/A	Not applicable: the ClinGen PTEN VCEP explicitly designates BP1 as not applicable.	cspec
BP2	Not assessed	Not assessed: no documented trans, cis, or phase-unknown observation with a different pathogenic or likely pathogenic PTEN variant is available.	cspec
BP3	N/A	Not applicable: the PTEN VCEP CSPEC explicitly marks BP3 as Not Applicable for this framework.	cspec
BP4	Not met	Not met: REVEL score 0.965 is above, rather than below, the PTEN VCEP BP4 missense threshold of <0.5.	cspec revel
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate disorder and non-overlapping personal or family histories are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of BP6 for this gene and framework.	cspec
BP7	N/A	Not applicable: p.(Thr131Ile) is a missense change, whereas PTEN VCEP BP7 covers only synonymous or qualifying intronic variants.	cspec

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